Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 5

Genetic MONDO:0013947 Pathograph 32 Show in embeddings browser neuronopathy, distal hereditary motor, autosomal recessive

Autosomal recessive distal hereditary motor neuronopathy type 5 (distal spinal muscular atrophy, autosomal recessive 5; DSMA5) is caused by biallelic loss-of-function variants in DNAJB2, which encodes HSJ1, a neuron-enriched J-domain co-chaperone of HSP70. HSJ1 stimulates the ATPase activity of HSP70 (HSPA8) and, through two C-terminal ubiquitin-interacting motifs, binds polyubiquitylated clients and the proteasome, so that it steers HSP70 clients to degradation by the ubiquitin-proteasome system rather than to refolding; the membrane-anchored HSJ1b isoform also takes part in ER-associated degradation. Reported alleles are splice-site, frameshift and deletion variants that abolish HSJ1 protein, plus rare missense changes. The founding family, a large Moroccan Jewish kindred, had a pure lower motor neuron disease with early-adult onset and predominantly lower-limb paralysis, and carried a homozygous splice-donor variant later shown to be a founder allele shared with Spanish families. Subsequent families showed that the same genotypes produce a continuum from pure distal motor neuropathy to axonal sensorimotor Charcot-Marie-Tooth disease type 2, with sensory loss commonly appearing with age and dHMN presentations evolving into CMT2. Onset is typically in the second decade; weakness and wasting begin in the distal legs, spread slowly to the proximal legs and hands, and lead to wheelchair dependence in severe families, with bulbar involvement at advanced stages. A minority of patients have early-onset parkinsonism with presynaptic dopaminergic deficit, and one family had sensorineural deafness. Which client proteins matter is not established; phospho-TDP-43 accumulation in patient skin and the potent anti-aggregation activity of HSJ1a toward TDP-43 and mutant SOD1 in experimental systems implicate failed clearance of aggregation-prone proteins.

Ask OpenScientist

Ask a research question about Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 5. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
20
Phenotypes
2
Gaps
32
Pathograph
1
Genes
4
Variants
4
Medical Actions
3
Differentials
11
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Both alleles must be inactivated; most patients are homozygous and several families are consanguineous. Heterozygous carriers with about 40% of normal protein were clinically unaffected in the Italian family.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:22522442 SUPPORT Human Clinical
"We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco."
Recessive inheritance in the founding family.
PMID:35286755 SUPPORT In Vitro
"Consistently, WB analysis showed an absence of DNAJB2 protein in the homozygous patient and a significant reduction of protein level in the heterozygous carrier (40% of the control's protein level; Figure 3a–b)."
Quantifies protein in an unaffected heterozygous carrier, consistent with recessive loss of function.
?

Discussions and Knowledge Gaps

2
Which HSJ1 client proteins and which downstream process link loss of HSJ1 to motor and sensory axon degeneration?
KNOWLEDGE GAP OPEN dnajb2_axon_loss_mechanism
Attached to
pathophysiology#Impaired Ubiquitin-Proteasome Targeting of HSP70 Client Proteins pathophysiology#Accumulation of Aggregation-Prone Client Proteins pathophysiology#Length-Dependent Degeneration of Lower Motor Neuron Axons
Every functional study of HSJ1 is an overexpression or construct experiment in non-neuronal or cultured neuronal cells, and the only patient tissue examined is skin, lymphoblastoid cells and fibroblasts. Phospho-TDP-43 in patient skin is the one direct link to a client protein, but loss of HSJ1 from dermal axons was not accompanied by neurofilament impairment. The review literature leaves open whether the lesion is proteotoxic or a defect of HSJ1b-dependent trafficking and secretion. No patient-derived motor neuron model or Dnajb2-null animal phenotype has been reported.
Show evidence (2 references)
PMID:35286755 SUPPORT Human Clinical
"Consistent with these data, skin biopsy analysis showed a complete loss of DNAJB2 expression in patients that was not associated with an impairment of NF, leaving the pathomechanism of the axonal loss still unclear."
The authors state the gap directly.
PMID:32093037 SUPPORT REVIEW SYNTHESIS Other
"The client protein(s) and processes relevant for the disease remain to be established: the pathomechanism could be envisioned to depend on cytotoxicity due to impaired protein quality control and turnover or a specific defect in protein trafficking or secretion caused by loss of DNAJB2b."
Names the two competing mechanistic hypotheses.
Are parkinsonism and other CNS features part of DNAJB2-related disease, or coincidental in a few families?
OPEN QUESTION OPEN dnajb2_cns_features_attribution
Attached to
pathophysiology#Nigrostriatal Dopaminergic Terminal Degeneration phenotypes#Parkinsonism
Parkinsonism with presynaptic dopaminergic deficit has now been reported in patients from several unrelated families with different alleles, including a compound heterozygote, and phospho-alpha-synuclein deposits were found in skin nerves of the patient with Parkinson disease but not in an affected sibling without parkinsonism. Against this, the numbers are very small, the deletion family's allele also overlaps a TUBA4A isoform, and the review literature considers the attribution unresolved.
Show evidence (2 references)
PMID:32093037 SUPPORT REVIEW SYNTHESIS Other
"Due to the small number of cases, it remains unclear whether the CNS symptoms in these patients are indeed due to the DNAJB2 mutations or additional factors"
States the uncertainty.
PMID:41799927 SUPPORT Human Clinical
"To our knowledge, this is the first case report describing the dual phenotype of CMT2 and young-onset PD linked to compound heterozygosity in DNAjB2."
An additional unrelated patient with the dual phenotype.
⚙

Pathophysiology

8
Biallelic DNAJB2 Loss-of-Function Variants
Mechanism confidence: Established
Two loss-of-function alleles of DNAJB2. The reported spectrum is dominated by splice-site variants (the c.352+1G>A founder allele, c.229+1G>A, c.446-1G>A and others), single-nucleotide deletions causing frameshift, and a 3.8 kb deletion removing the exons that encode the J domain, with a small number of missense changes such as c.14A>G p.(Tyr5Cys) in the J domain. Most patients are homozygous, often from consanguineous families; compound heterozygosity is reported.
DNAJB2 hgnc:5228 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAJB2 (hgnc:5228). hgnc:5228 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Biallelic germline loss of function, usually homozygous; one compound heterozygous patient (c.352+1G>A with c.175+2T>A) has been reported.
Downstream
Loss of HSJ1 Co-chaperone Protein Splice-site variants cause intron retention and premature termination, and a frameshift allele abolishes the protein; patient fibroblasts, lymphoblastoid cells and skin show reduced transcript and absent or severely reduced HSJ1 protein.
Show evidence (3 references)
PMID:22522442 SUPPORT Human Clinical
"We mapped the disease to the 2q34-q36.1 chromosomal region and identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b."
The founding family; homozygosity mapping identifies a homozygous DNAJB2 splice variant that lowers expression of both isoforms.
PMID:42806108 SUPPORT Human Clinical
"In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state."
Systematic review establishing the size of the allelic series and the predominance of homozygous genotypes.
PMID:41799927 SUPPORT Human Clinical
"Genetic test revealed compound heterozygous pathogenic variants in DNAjB2 (c.352+1 G>A and c.175+2T>A)."
Documents that compound heterozygous genotypes also cause disease.
Loss of HSJ1 Co-chaperone Protein
Mechanism confidence: Established
Absence of both HSJ1 isoforms: HSJ1a (277 aa, cytosolic and nuclear) and HSJ1b (324 aa, geranylgeranyl-anchored to the cytoplasmic face of the endoplasmic reticulum, the predominant isoform in neurons). Each carries an N-terminal J domain that binds HSP70 and stimulates its ATPase activity, and two C-terminal ubiquitin-interacting motifs that bind polyubiquitin chains and the proteasome. Loss of the protein therefore removes an HSP70 ATPase activator, an HSP70-binding client-delivery factor and a polyubiquitin-binding adaptor at once. Expression is highest in neurons, which fits the neural restriction of the disease.
DNAJB2 hgnc:5228 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAJB2 (hgnc:5228). hgnc:5228 is a gene from the HUGO Gene Nomenclature Committee.
HSJ1 J-domain stimulation of HSP70 ATPase activity GO:0001671 ∅ ABSENT Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves absent HSJ1 J-domain stimulation of HSP70 ATPase activity, annotated with ATPase activator activity (GO:0001671). GO:0001671 is a molecular function from the Gene Ontology. HSJ1 J-domain binding to HSP70 GO:0030544 ∅ ABSENT Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves absent HSJ1 J-domain binding to HSP70, annotated with Hsp70 protein binding (GO:0030544). GO:0030544 is a molecular function from the Gene Ontology. HSJ1 ubiquitin-interacting motif binding to polyubiquitylated clients GO:0031593 ∅ ABSENT Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves absent HSJ1 ubiquitin-interacting motif binding to polyubiquitylated clients, annotated with polyubiquitin modification-dependent protein binding (GO:0031593). GO:0031593 is a molecular function from the Gene Ontology. HSJ1 ubiquitin-interacting motif binding to the proteasome GO:0070628 ∅ ABSENT Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves absent HSJ1 ubiquitin-interacting motif binding to the proteasome, annotated with proteasome binding (GO:0070628). GO:0070628 is a molecular function from the Gene Ontology.
Downstream
Impaired Ubiquitin-Proteasome Targeting of HSP70 Client Proteins Inferred from HSJ1 function in overexpression and cell systems: HSJ1 directs HSP70 clients to the proteasome rather than to refolding, so its absence is expected to slow client degradation. Impaired degradation has not been measured directly in patient neurons.
Accumulation of Aggregation-Prone Client Proteins Separately from proteasomal targeting, HSJ1a keeps TDP-43 soluble by a J-domain-dependent, proteasome-independent route, so loss of HSJ1 is expected to remove anti-aggregation activity as well as degradative activity.
Show evidence (6 references)
PMID:32093037 SUPPORT REVIEW SYNTHESIS In Vitro
"both isoforms have been shown to stimulate the ATPase activity of HSPA8 and to modulate its client binding"
Grounds the ATPase activator activity and HSP70 client-binding role that patients lose.
PMID:32093037 SUPPORT REVIEW SYNTHESIS In Vitro
"As a unique feature among human J proteins, the C-terminal region of DNAJB2 harbors two ubiquitin interaction motifs (UIMs) that mediate binding to polyubiquitylated proteins and to the proteasome"
Grounds the polyubiquitin-binding and proteasome-binding functions.
PMID:21625540 SUPPORT In Vitro
"This dual regulation is dependent on the binding of the J-domain with HSP70, and the UIM domain with polyUb chains."
Primary cell data showing the J domain binds HSP70 and the UIMs bind polyubiquitin chains.
+ 3 more references
Impaired Ubiquitin-Proteasome Targeting of HSP70 Client Proteins
Mechanism confidence: Provisional
HSJ1 promotes ubiquitylation of HSP70-bound clients by STUB1 (CHIP), protects the chains from deubiquitylation and delivers the clients to the proteasome; HSJ1b additionally promotes ER-associated degradation of membrane and secretory proteins. In cell and animal systems, HSJ1 overexpression increases client ubiquitylation and degradation and lowers inclusion formation by polyglutamine proteins and mutant SOD1. The disease-relevant client proteins are not known, and impaired degradation has been inferred rather than measured in patient tissue.
lower motor neuron CL:0008039 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lower motor neuron (CL:0008039). CL:0008039 is a cell type from the Cell Ontology.
proteasomal degradation of HSP70 client proteins GO:0043161 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteasomal degradation of HSP70 client proteins, annotated with proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). GO:0043161 is a biological process from the Gene Ontology. chaperone-mediated quality control of misfolded proteins GO:0006515 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chaperone-mediated quality control of misfolded proteins, annotated with protein quality control for misfolded or incompletely synthesized proteins (GO:0006515). GO:0006515 is a biological process from the Gene Ontology. HSJ1b-dependent ER-associated degradation GO:0036503 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased HSJ1b-dependent ER-associated degradation, annotated with ERAD pathway (GO:0036503). GO:0036503 is a biological process from the Gene Ontology.
Downstream
Accumulation of Aggregation-Prone Client Proteins Clients not routed to degradation are expected to accumulate and aggregate; supported by gain-of-function experiments in which HSJ1 lowers inclusion formation.
Show evidence (6 references)
PMID:17426712 SUPPORT In Vitro
"Together these results show that HSJ1 proteins mediated an increase in target protein degradation via the ubiquitin-proteasome system (UPS)."
Primary evidence that HSJ1 drives client degradation through the proteasome.
PMID:17426712 SUPPORT In Vitro
"In contrast, expression of HSJ1 proteins did not promote chaperone activity but caused an increase in ubiquitylation."
Distinguishes the degradative from the refolding function of HSJ1.
PMID:37070754 SUPPORT BACKGROUND In Vitro
"DNAJB2 interacts with polyubiquitinated proteins and the proteasome through its UIMs, and cooperates with STUB1 (CHIP) to promote client ubiquitination and sorting to UPS"
Summarises the STUB1-dependent ubiquitylation and proteasomal sorting route.
+ 3 more references
Accumulation of Aggregation-Prone Client Proteins
Mechanism confidence: Provisional
In the one family studied, immunoblots of skin biopsies detected phospho-TDP-43 in two affected siblings (II.1 and II.2) and not in a single control; this shows the presence of the phosphorylated protein, not aggregates. Immunohistochemistry found phospho-alpha-synuclein deposits along dermal nerve fibres in one patient, the proband with Parkinson disease, while an affected sibling without parkinsonism was negative. These are the only patient-tissue observations bearing on protein accumulation; whether the same proteins accumulate in motor neurons is not known.
Downstream
Length-Dependent Degeneration of Lower Motor Neuron Axons Proposed but unproven: the authors attribute neuropathy to failed removal of toxic aggregates, yet HSJ1 loss in dermal axons was not accompanied by neurofilament impairment and the step from proteostatic failure to axon loss is unknown.
Length-Dependent Sensory Axon Loss The same unknown intermediates are presumed to account for the later involvement of sensory axons.
Nigrostriatal Dopaminergic Terminal Degeneration Hypothesised from phospho-alpha-synuclein deposits in the one patient with Parkinson disease in whom skin was examined; the link is not established.
Show evidence (3 references)
PMID:35286755 SUPPORT Human Clinical
"Consistent with these data, we demonstrated TDP-43 accumulation in patients' skin but not in the control, supporting the hypothesis that in our patients the loss of DNAJB2 impairs the removal of toxic protein aggregates."
Patient-tissue evidence of TDP-43 accumulation with loss of HSJ1.
PMID:35286755 SUPPORT Human Clinical
"Notably, IHC study of the proband's skin biopsy showed abnormal accumulation of p-alpha-syn along the nerve fiber, which was absent in the control"
Phospho-alpha-synuclein accumulation in the patient with parkinsonism.
PMID:26936937 SUPPORT INDIRECT In Vitro
"To determine which chaperones were mediating TDP-43 clearance we over-expressed a range of heat shock proteins (HSPs) and identified DNAJB2a (encoded by DNAJB2, and also known as HSJ1a) as a potent anti-aggregation chaperone for TDP-43."
Identifies TDP-43 as an HSJ1a client, which makes its accumulation in patient tissue mechanistically plausible.
Length-Dependent Degeneration of Lower Motor Neuron Axons
Mechanism confidence: Established
Degeneration of lower motor neurons and their long axons, affecting the longest lower-limb motor axons first. The founding family had a pure lower motor neuron disease; nerve conduction shows a motor axonal pattern, and needle EMG shows chronic denervation with very large motor unit potentials. No spinal cord pathology from a patient has been reported, so the relative contributions of cell body and axon are not established.
lower motor neuron CL:0008039 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lower motor neuron (CL:0008039). CL:0008039 is a cell type from the Cell Ontology. spinal cord motor neuron CL:0011001 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spinal cord motor neuron (CL:0011001). CL:0011001 is a cell type from the Cell Ontology.
ventral horn of spinal cord UBERON:0002257 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ventral horn of spinal cord (UBERON:0002257). UBERON:0002257 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Chronic Neurogenic Denervation of Distal Limb Muscle Loss of motor axons denervates the muscles they supply, beginning in the distal leg.
Motor axonal neuropathy Motor axon loss is what the nerve conduction finding measures.
Peripheral axonal neuropathy Motor axon loss is the motor half of the length-dependent axonal motor and sensory polyneuropathy recorded on nerve conduction in the CMT2 presentation.
Absent Achilles reflex Loss of the longest motor axons interrupts the efferent limb of the ankle stretch reflex first, consistent with the length-dependent pattern.
Hyporeflexia More widespread motor axon loss diminishes tendon reflexes beyond the ankle.
Dysphagia Bulbar involvement is reported mainly at an advanced stage; bulbar motor neuron involvement is the presumed route, but no bulbar pathology or electrophysiology has been reported in this disease.
Respiratory insufficiency Respiratory involvement is reported only at an advanced stage, alongside bulbar symptoms; extension of motor neuron loss to respiratory muscles is the presumed route, and the intermediates are not documented.
Show evidence (2 references)
PMID:22522442 SUPPORT Human Clinical
"Interestingly, this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons."
Establishes the lower motor neuron as the primary target in the founding family.
PMID:27449489 SUPPORT Human Clinical
"Electromyography (EMG) and nerve conduction testing revealed an active chronic motor neuron axonal disorder with huge motor unit action potentials (MUAPs) compatible with a SMA."
Electrophysiological evidence of chronic lower motor neuron and axon loss.
Length-Dependent Sensory Axon Loss
Mechanism confidence: Established
Loss of large-calibre sensory fibres, typically appearing later than the motor deficit and converting a dHMN presentation into axonal CMT2. Sural nerve biopsy in one patient showed reduced fibre density, mainly of large fibres, with acute axonal degeneration and rare regeneration clusters.
Downstream
Distal sensory impairment Sensory axon loss produces the distal sensory deficit.
Peripheral axonal neuropathy Sensory axon loss added to the motor deficit is what turns the dHMN picture into the axonal motor and sensory polyneuropathy of CMT2.
Absent Achilles reflex Loss of large-calibre sensory fibres removes the afferent limb of the ankle stretch reflex.
Hyporeflexia Large-fibre sensory loss also contributes to the more widespread reduction in tendon reflexes.
Show evidence (2 references)
PMID:35286755 SUPPORT Human Clinical
"Sural nerve biopsy in patient II.1, at the age of 36 years, disclosed a moderate reduction of nerve fiber density, mainly involving the large-caliber fibers."
Direct histological evidence of sensory nerve fibre loss.
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"Sensory symptoms such as decreased sensation appear with age in many if not all patients"
Records the age-dependent emergence of sensory involvement across reported families.
Chronic Neurogenic Denervation of Distal Limb Muscle
Mechanism confidence: Established
Denervation atrophy and fatty replacement of distal leg muscles, affecting anterior and posterior leg compartments more than the thigh, and later the proximal legs and hands.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Distal lower limb muscle weakness
Distal lower limb amyotrophy
Proximal lower limb muscle weakness
Distal upper limb muscle weakness
Pes cavus Foot deformity is attributed to the neuropathy; the authors of the cohort read pes cavus and scoliosis as reflecting its severity.
Scoliosis Scoliosis is reported alongside pes cavus in the same series and is read the same way, as a consequence of the neuromuscular weakness rather than a primary skeletal defect; the intermediate steps are not described.
Gait disturbance Distal leg weakness from denervation is the source of the gait difficulty that is the usual presenting symptom.
Loss of ambulation Progressive denervation spreading from distal to proximal leg muscles leads to wheelchair dependence in severely affected patients.
Show evidence (1 reference)
PMID:35286755 SUPPORT Human Clinical
"In the proband, muscle CT showed severe fatty replacement of both the anterior and posterior compartments of the leg more than the thigh muscles"
Imaging evidence of distal-predominant muscle denervation change.
Nigrostriatal Dopaminergic Terminal Degeneration
Mechanism confidence: Provisional
Presynaptic dopaminergic deficit on dopamine transporter imaging in the patients with parkinsonism, one with juvenile onset at 16 years and one with typical Parkinson disease at 50 years. Whether this is caused by DNAJB2 loss or is coincidental is debated, given the small number of cases.
dopaminergic neuron CL:0000700 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dopaminergic neuron (CL:0000700). CL:0000700 is a cell type from the Cell Ontology.
Downstream
Parkinsonism
Show evidence (2 references)
PMID:35286755 SUPPORT Human Clinical
"while DaT-Scan disclosed a severe, bilateral but asymmetric reduction of tracer uptake indicative of presynaptic dopaminergic terminal degeneration"
Imaging evidence of dopaminergic terminal loss in the proband with Parkinson disease.
PMID:27449489 SUPPORT Human Clinical
"Dopamine transporter imaging (TRODAT SPECT scan) showed markedly decreased presynaptic dopamine activity in the striata, more severe on the right side (Fig. 1B)."
Independent imaging evidence in the patient with juvenile parkinsonism.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 5 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

20
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41549766 SUPPORT Human Clinical
"Bulbar dysfunction with mild dysphagia was present in two patients (P2, P3)."
Bulbar dysphagia in two patients.
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"Bulbar and respiratory symptoms may develop at the advanced stage"
Bulbar involvement is a late feature.
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35286755 SUPPORT Human Clinical
"Additionally, all patients had deafness, starting in the third or fourth decade of life."
Deafness in all affected members of one family.
Limbs 5
Distal lower limb muscle weakness HP:0009053 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal lower limb muscle weakness (HP:0009053). HP:0009053 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:22522442 SUPPORT Human Clinical
"The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset."
Lower-limb predominant paralysis in the founding family.
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"which manifests as pareses, muscle weakness, and atrophy appearing first in distal lower limbs and progressing slowly to proximal lower limbs and arms"
Synthesises the distal lower-limb onset across reported families.
PMID:35286755 SUPPORT Human Clinical
"Clinical examination showed mild-to-moderate distal paresis in the upper limbs, a severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles."
Complete distal leg paralysis in an advanced family.
Proximal lower limb muscle weakness HP:0008994 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal lower limb muscle weakness (HP:0008994). HP:0008994 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35286755 SUPPORT Human Clinical
"The disease onset occurred in the second or third decade of life, with gait difficulty and progressive weakness in the lower limbs, first distally and then proximally."
Documents the distal-to-proximal spread of leg weakness.
Distal upper limb muscle weakness HP:0008959 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal upper limb muscle weakness (HP:0008959). HP:0008959 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35286755 SUPPORT Human Clinical
"Clinical examination showed mild-to-moderate distal paresis in the upper limbs, a severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles."
Distal upper limb paresis, milder than the leg involvement.
Absent Achilles reflex HP:0003438 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent Achilles reflex (HP:0003438). HP:0003438 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41549766 SUPPORT Human Clinical
"Ankle | Absent | Absent | Absent | Absent | Absent | Absent"
Table 1 row recording absent ankle reflexes in all six DNAJB2 patients.
PMID:35286755 SUPPORT Human Clinical
"Ankle deep tendon reflexes | Absent | Absent | Absent"
Table 1 row recording absent ankle reflexes in all three affected siblings.
Pes cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41549766 SUPPORT Human Clinical
"All six patients had pes cavus; five had scoliosis (P2-6)."
Pes cavus in 6 of 6 patients.
Musculoskeletal 3
Distal lower limb amyotrophy HP:0008944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal lower limb amyotrophy (HP:0008944). HP:0008944 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"which manifests as pareses, muscle weakness, and atrophy appearing first in distal lower limbs and progressing slowly to proximal lower limbs and arms"
Atrophy begins in the distal lower limbs.
PMID:27449489 SUPPORT Human Clinical
"had muscle atrophy of all four limbs, more marked distally, and diminished reflexes"
Distal-predominant wasting in the deletion family.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41549766 SUPPORT Human Clinical
"All six patients had pes cavus; five had scoliosis (P2-6)."
Scoliosis in 5 of 6 patients.
Rimmed vacuoles HP:0003805 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rimmed vacuolar myopathy, annotated with Rimmed vacuoles (HP:0003805). HP:0003805 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37070754 SUPPORT BACKGROUND Human Clinical
"Recently, rimmed-vacuolar myopathy in combination with dHMN was described in a patient homozygous for a DNAJB2 missense mutation"
States the rimmed-vacuolar finding in a recessive DNAJB2 patient.
PMID:35652544 SUPPORT Human Clinical
"Here, we report a dHMN patient due to a homozygous c.184C>T variant in the DNAJB2 gene with rare neuropathic and myopathic characteristics on pathological examination."
The primary case report of combined neuropathic and myopathic pathology.
Nervous System 9
Gait disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35286755 SUPPORT Human Clinical
"The disease onset occurred in the second or third decade of life, with gait difficulty and progressive weakness in the lower limbs, first distally and then proximally."
Gait difficulty at onset.
Motor axonal neuropathy HP:0007002 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor axonal neuropathy (HP:0007002). HP:0007002 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41549766 SUPPORT Human Clinical
"Among the five patients with the DNAJB2 c.446-1G>A homozygous variant, four showed an axonal motor neuropathy on NCS, while one displayed an axonal motor and sensory neuropathy."
Gives the proportion with a motor-only axonal pattern in one family.
Peripheral axonal neuropathy HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axonal sensorimotor polyneuropathy, annotated with Peripheral axonal neuropathy (HP:0003477). HP:0003477 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35286755 SUPPORT Human Clinical
"Nerve conduction studies showed an axonal motor and sensory length-dependent polyneuropathy."
Sensorimotor axonal neuropathy in a CMT2 family.
PMID:28018906 SUPPORT REVIEW SYNTHESIS Human Clinical
"The patients in Spain displayed a dHMN or CMT2 phenotype and, in some cases, initial clinical manifestations that were consistent with dHMN and that subsequently evolved to CMT2 (Frasquet et al., 2016)."
Records the evolution of dHMN into CMT2 in founder-allele families.
Distal sensory impairment HP:0002936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal sensory impairment (HP:0002936). HP:0002936 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35286755 SUPPORT Human Clinical
"Joint position, vibration and superficial sensation were reduced in the lower limbs."
Distal sensory loss on examination.
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"Sensory symptoms such as decreased sensation appear with age in many if not all patients"
Sensory loss is common and age-dependent.
Hyporeflexia HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27449489 SUPPORT Human Clinical
"had muscle atrophy of all four limbs, more marked distally, and diminished reflexes"
Diminished reflexes in the two siblings with axonal sensorimotor neuropathy.
PMID:41549766 SUPPORT Human Clinical
"Biceps | Diminished | Diminished | Diminished | Diminished | Diminished | Absent"
Table 1 row showing diminished or absent biceps reflexes in all six patients.
Loss of ambulation HP:0002505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Loss of ambulation (HP:0002505). HP:0002505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35286755 SUPPORT Human Clinical
"All patients were wheelchair-bound from their fifth to sixth decade of life."
Loss of ambulation in all affected members of one family.
Parkinsonism HP:0001300 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Parkinsonism (HP:0001300). HP:0001300 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:27449489 SUPPORT Human Clinical
"who at the age of 16 presented with a coarse resting tremor and rigidity, which gradually progressed"
Juvenile parkinsonism in the deletion family.
PMID:35286755 SUPPORT Human Clinical
"The proband developed typical PD at the age of 50 years, with asymmetric resting tremor, rigidity and hypokinesia responsive to L-DOPA treatment."
Later-onset Parkinson disease in the frameshift family.
PMID:41799927 SUPPORT Human Clinical
"We present a 36-year-old female patient initially diagnosed with CMT2 at the age of 28, who later developed symptoms of PD in her fourth decade."
Young-onset Parkinson disease after CMT2 in a compound heterozygote.
+ 1 more reference
Postural tremor HP:0002174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postural tremor (HP:0002174). HP:0002174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41549766 SUPPORT Human Clinical
"Mild postural tremor was observed in two patients (P5, P6)."
Postural tremor in 2 of 6 DNAJB2 patients.
Restless legs HP:0012452 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restless legs (HP:0012452). HP:0012452 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41549766 SUPPORT Human Clinical
"restless legs syndrome was observed in four patients with a DNAJB2 variant but in none with a HINT1"
Restless legs in four DNAJB2 patients.
Respiratory 1
Respiratory insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"Bulbar and respiratory symptoms may develop at the advanced stage"
Review-level statement that respiratory symptoms are a late feature.
🧬

Genetic Associations

1
DNAJB2 (Biallelic loss-of-function variants in DNAJB2 are the only established cause. In a Spanish dHMN cohort DNAJB2 was the fourth most frequent cause, accounting for 6.7% of patients.)
Gene: DNAJB2 hgnc:5228 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNAJB2 (hgnc:5228). hgnc:5228 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:25274842 SUPPORT Human Clinical
"Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population."
Segregation evidence in two further families.
PMID:25274842 SUPPORT Human Clinical
"we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2"
Cohort-level confirmation of the gene-disease relationship.
PMID:35286755 SUPPORT Human Clinical
"Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease."
Segregation of a null allele in a third independent family.
+ 2 more references
Variants (4)
NM_006736.6:c.352+1G>A Pathogenic
Gene: DNAJB2 hgnc:5228 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DNAJB2 (hgnc:5228). hgnc:5228 is a gene from the HUGO Gene Nomenclature Committee.
Splice-donor variant reported homozygous in the founding Moroccan Jewish family and in Spanish families, where haplotype analysis showed a shared founder haplotype; also reported in a Brazilian family and, in compound heterozygosity, in a patient with CMT2 and young-onset Parkinson disease. It causes intron retention and severely reduced protein in patient fibroblasts.
Show evidence (3 references)
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"who identified a homozygous c.352+1G>A splice donor site mutation in a family with dHMN"
The sentence, which in the review continues the attribution to Blumen and colleagues, names the splice-donor allele of the first reported dHMN family.
PMID:28018906 SUPPORT REVIEW SYNTHESIS Human Clinical
"Hence, the DNAJB2 c.352+1G>A mutation appears to be a founder event (Lupo et al., 2016), and it is shared with a family reported elsewhere (Blumen et al., 2012)."
Establishes the founder status of the allele.
PMID:26752306 SUPPORT Human Clinical
"On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event."
Primary haplotype evidence for the founder allele in five Spanish families.
NM_006736.6:c.229+1G>A Pathogenic
Gene: DNAJB2 hgnc:5228 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DNAJB2 (hgnc:5228). hgnc:5228 is a gene from the HUGO Gene Nomenclature Committee.
Homozygous splice-donor variant in a dHMN family causing retention of intron 4, a premature stop codon and loss of protein.
Show evidence (2 references)
PMID:25274842 SUPPORT Human Clinical
"One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A"
Phenotype and zygosity of the allele in the reported family.
PMID:25274842 SUPPORT In Vitro
"which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression"
Patient fibroblast RNA and protein result establishing the molecular consequence.
NM_006736.6:c.145del p.(Val49TrpfsTer25) Pathogenic
Gene: DNAJB2 hgnc:5228 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DNAJB2 (hgnc:5228). hgnc:5228 is a gene from the HUGO Gene Nomenclature Committee.
Homozygous single-nucleotide deletion (reported as c.145delG) in the J domain, causing a frameshift and absent protein in an Italian CMT2 family with deafness and parkinsonism.
Show evidence (1 reference)
PMID:35286755 SUPPORT Human Clinical
"The CMT gene panel analysis in the proband (II.2) revealed the novel homozygous pathogenic variant c.145delG in the DNAJB2 gene (NM_006736.6), resulting in the frameshift p. Val49TrpfsTer25."
Identifies the allele and its consequence.
3.8 kb deletion of the 5' DNAJB2 exons Pathogenic
Gene: DNAJB2 hgnc:5228 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DNAJB2 (hgnc:5228). hgnc:5228 is a gene from the HUGO Gene Nomenclature Committee.
Homozygous ~3.8 kb deletion removing the first coding exons, which encode the J domain, found by whole-genome sequencing in a consanguineous family with SMA-like distal motor neuropathy, axonal sensorimotor neuropathy in two siblings and juvenile parkinsonism in one. It most likely abolishes expression; it also overlaps a predicted TUBA4A isoform.
Show evidence (2 references)
PMID:27449489 SUPPORT Human Clinical
"After performing homozygosity mapping and whole genome sequencing, we identified a 3.8 kb deletion, spanning the entire DnaJ domain of the HSJ1 protein, as the disease-segregating mutation."
Identifies the structural allele and its segregation.
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"Moreover, the deletion also affects a predicted isoform of the TUBA4A gene, mutations in which are associated with ALS"
Records the overlap with TUBA4A as a possible contributor to the phenotype.
💊

Medical Actions

4
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Supportive physiotherapy and rehabilitation for distal weakness and gait impairment. No disease-modifying therapy exists.
Target Phenotypes: Distal lower limb muscle weakness HP:0009053 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Distal lower limb muscle weakness (HP:0009053). HP:0009053 is a phenotype from the Human Phenotype Ontology. Gait disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Ankle-Foot Orthosis for Distal Leg Weakness
Action: ankle-foot orthosis fittingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is ankle-foot orthosis fitting, annotated with Rehabilitation (NCIT:C15315), qualified as medical device ankle-foot orthosis. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Orthotic support for distal leg weakness. The device concept is carried as a qualifier because NCIT's Brace term is a medical device and cannot sit in the treatment_term slot.
Target Phenotypes: Distal lower limb muscle weakness HP:0009053 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Distal lower limb muscle weakness (HP:0009053). HP:0009053 is a phenotype from the Human Phenotype Ontology.
Levodopa for Associated Parkinsonism
Action: levodopa pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is levodopa pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: levodopa CHEBI:15765 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levodopa, annotated with L-dopa (CHEBI:15765). CHEBI:15765 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Levodopa has been used for the parkinsonism seen in a minority of patients, with a good response in a patient with typical Parkinson disease at 50 years and only a slight, transient response in a patient with juvenile parkinsonism.
Target Phenotypes: Parkinsonism HP:0001300 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Parkinsonism (HP:0001300). HP:0001300 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35286755 SUPPORT Human Clinical
"The proband developed typical PD at the age of 50 years, with asymmetric resting tremor, rigidity and hypokinesia responsive to L-DOPA treatment."
Levodopa-responsive parkinsonism in one patient.
PMID:27449489 SUPPORT Human Clinical
"At 1-year follow-up, his tremor no longer responded to levodopa treatment."
Loss of levodopa response in the juvenile-onset patient.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Counselling for an autosomal recessive condition in which consanguinity is common and a founder splice allele recurs in Moroccan Jewish and Spanish families. Heterozygous carriers are unaffected.
Show evidence (1 reference)
PMID:25274842 SUPPORT Human Clinical
"Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population."
Autosomal recessive segregation is the basis of the recurrence risk and carrier counselling.
🔬

Diagnosis

2
Nerve conduction studies and needle electromyography
Nerve conduction shows a length-dependent axonal pattern, pure motor in dHMN presentations and sensorimotor in CMT2 presentations; needle EMG shows chronic denervation with very large motor unit potentials.
nerve conduction studies NCIT:C88502 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27449489 SUPPORT Human Clinical
"Electromyography (EMG) and nerve conduction testing revealed an active chronic motor neuron axonal disorder with huge motor unit action potentials (MUAPs) compatible with a SMA."
The electrodiagnostic finding that frames the disease as a distal SMA.
Multigene neuropathy panel sequencing
The diagnosis is made by finding biallelic DNAJB2 variants, typically on a CMT/hereditary motor neuropathy gene panel or exome. In a Spanish cohort screened with a 56-gene panel, the c.352+1G>A founder allele was found in two index cases and then in three further families. The 3.8 kb deletion was found by whole-genome sequencing, so copy-number-aware analysis is needed when sequencing finds a single or no variant.
multigene neuropathy panel NCIT:C198412 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:26752306 SUPPORT Human Clinical
"We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy."
Describes the panel through which DNAJB2 patients were identified.
PMID:26752306 SUPPORT Human Clinical
"The DNAJB2 c.352+1G>A mutation was detected in two cases"
Panel yield for DNAJB2 in the cohort.
📈

Progression

2
Adolescent to early adult onset
Age: late first to early fourth decade
Onset is typically in the second decade, with a reported range from the late first to the early fourth decade, usually with gait difficulty and distal leg weakness.
Show evidence (2 references)
PMID:32093037 SUPPORT REVIEW SYNTHESIS Human Clinical
"The onset of symptoms is typically in the 2nd decade of life, and has been reported to range from the late 1st to early 4th decades"
Age-of-onset range across reported families.
PMID:41549766 SUPPORT Human Clinical
"Most patients developed symptoms during late adolescence, with initial manifestation occurring in the lower limbs in all cases."
Late-adolescent onset in the lower limbs in a recent series.
Slow progression with proximal and sensory spread
Age: second decade onward
Motor function declines slowly and continuously; in one family the MRC sum score fell by an average of 0.78 points per year over up to 10 years of follow-up. Weakness spreads to the proximal legs and the hands, sensory involvement appears, and severely affected patients become wheelchair-bound by the fifth to sixth decade, with bulbar involvement at advanced stages.
Show evidence (2 references)
PMID:41549766 SUPPORT Human Clinical
"Over the observation period, motor function declined on average by 0.78 points per year (on MRC-SS scale)"
The only quantitative natural-history estimate.
PMID:35286755 SUPPORT Human Clinical
"All patients were wheelchair-bound from their fifth to sixth decade of life."
Late-stage loss of ambulation in a severe family.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population prevalence has been published. A 2026 systematic review counted 46 reported families carrying 25 distinct variants. That is a case count, not a prevalence.
Show evidence (1 reference)
PMID:42806108 SUPPORT Human Clinical
"In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state."
Gives the number of reported families.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 5:

Perry syndrome (DCTN1)
Overlapping Features Relevant when parkinsonism accompanies the neuropathy: DCTN1 causes both a distal motor neuropathy and Perry syndrome, which combines early-onset parkinsonism with TDP-43 proteinopathy.
Distinguishing Features
  • Perry syndrome adds depression or apathy and central hypoventilation.
Show evidence (1 reference)
PMID:35286755 SUPPORT BACKGROUND Human Clinical
"It is characterized clinically by early-onset parkinsonism, depression/apathy and central hypoventilation, and pathologically by degeneration of dopaminergic neurons and TDP-43 proteinopathy"
The authors' comparison of Perry syndrome with the DNAJB2 phenotype.
{ }

Source YAML

click to show 
name: Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 5
creation_date: "2026-10-01T00:00:00Z"
category: Genetic
description: >
  Autosomal recessive distal hereditary motor neuronopathy type 5 (distal
  spinal muscular atrophy, autosomal recessive 5; DSMA5) is caused by biallelic
  loss-of-function variants in DNAJB2, which encodes HSJ1, a neuron-enriched
  J-domain co-chaperone of HSP70. HSJ1 stimulates the ATPase activity of HSP70
  (HSPA8) and, through two C-terminal ubiquitin-interacting motifs, binds
  polyubiquitylated clients and the proteasome, so that it steers HSP70 clients
  to degradation by the ubiquitin-proteasome system rather than to refolding;
  the membrane-anchored HSJ1b isoform also takes part in ER-associated
  degradation. Reported alleles are splice-site, frameshift and deletion
  variants that abolish HSJ1 protein, plus rare missense changes. The founding
  family, a large Moroccan Jewish kindred, had a pure lower motor neuron disease
  with early-adult onset and predominantly lower-limb paralysis, and carried a
  homozygous splice-donor variant later shown to be a founder allele shared with
  Spanish families. Subsequent families showed that the same genotypes produce a
  continuum from pure distal motor neuropathy to axonal sensorimotor
  Charcot-Marie-Tooth disease type 2, with sensory loss commonly appearing with
  age and dHMN presentations evolving into CMT2. Onset is typically in the
  second decade; weakness and wasting begin in the distal legs, spread slowly to
  the proximal legs and hands, and lead to wheelchair dependence in severe
  families, with bulbar involvement at advanced stages. A minority of patients
  have early-onset parkinsonism with presynaptic dopaminergic deficit, and one
  family had sensorineural deafness. Which client proteins matter is not
  established; phospho-TDP-43 accumulation in patient skin and the potent
  anti-aggregation activity of HSJ1a toward TDP-43 and mutant SOD1 in
  experimental systems implicate failed clearance of aggregation-prone proteins.
disease_term:
  preferred_term: DNAJB2-related distal hereditary motor neuronopathy
  term:
    id: MONDO:0013947
    label: neuronopathy, distal hereditary motor, autosomal recessive 5
synonyms:
- DSMA5
- dSMA5
- autosomal recessive distal spinal muscular atrophy type 5
- DNAJB2-related CMT2
- young adult-onset distal hereditary motor neuropathy
- Young adult-onset dHMN
parents:
- neuronopathy, distal hereditary motor, autosomal recessive
references:
- reference: PMID:22522442
  title: "A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation."
- reference: PMID:25274842
  title: "HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum."
- reference: PMID:27449489
  title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
- reference: PMID:35286755
  title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
- reference: PMID:41549766
  title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
- reference: PMID:42806108
  title: "Variable phenotypic manifestations of two splice-site variants in DNAJB2: insights from two families and a systematic review."
- reference: PMID:32093037
  title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
- reference: PMID:28018906
  title: "Chaperonopathies: Spotlight on Hereditary Motor Neuropathies."
- reference: PMID:37070754
  title: "Extension of the DNAJB2a isoform in a dominant neuromyopathy family."
- reference: PMID:26752306
  title: "Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy."
- reference: PMID:27083531
  title: "Phenotype and natural history of inherited neuropathies caused by HSJ1 c.352+1G>A mutation."
pathophysiology:
- name: Biallelic DNAJB2 Loss-of-Function Variants
  biological_scale: MOLECULAR
  role: initiating genetic lesion
  mechanism_confidence: ESTABLISHED
  description: >
    Two loss-of-function alleles of DNAJB2. The reported spectrum is dominated
    by splice-site variants (the c.352+1G>A founder allele, c.229+1G>A,
    c.446-1G>A and others), single-nucleotide deletions causing frameshift, and
    a 3.8 kb deletion removing the exons that encode the J domain, with a small
    number of missense changes such as c.14A>G p.(Tyr5Cys) in the J domain.
    Most patients are homozygous, often from consanguineous families; compound
    heterozygosity is reported.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline loss of function, usually homozygous; one compound
      heterozygous patient (c.352+1G>A with c.175+2T>A) has been reported.
  genes:
  - preferred_term: DNAJB2
    term:
      id: hgnc:5228
      label: DNAJB2
  evidence:
  - reference: PMID:22522442
    reference_title: "A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We mapped the disease to the 2q34-q36.1 chromosomal region and identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b."
    explanation: The founding family; homozygosity mapping identifies a homozygous DNAJB2 splice variant that lowers expression of both isoforms.
  - reference: PMID:42806108
    reference_title: "Variable phenotypic manifestations of two splice-site variants in DNAJB2: insights from two families and a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state."
    explanation: Systematic review establishing the size of the allelic series and the predominance of homozygous genotypes.
  - reference: PMID:41799927
    reference_title: "Co-Existing Charcot-Marie-Tooth Disease Type II and Parkinson's Disease Linked to a Novel DNAjB2 Pathogenic Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic test revealed compound heterozygous pathogenic variants in DNAjB2 (c.352+1 G>A and c.175+2T>A)."
    explanation: Documents that compound heterozygous genotypes also cause disease.
  downstream:
  - target: Loss of HSJ1 Co-chaperone Protein
    causal_link_type: DIRECT
    description: >-
      Splice-site variants cause intron retention and premature termination,
      and a frameshift allele abolishes the protein; patient fibroblasts,
      lymphoblastoid cells and skin show reduced transcript and absent or
      severely reduced HSJ1 protein.
    evidence:
    - reference: PMID:25274842
      reference_title: "HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression"
      explanation: Patient fibroblast RNA and protein studies link a splice allele directly to loss of HSJ1 protein.
    - reference: PMID:35286755
      reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy."
      explanation: A homozygous frameshift allele abolishes HSJ1 protein in patient lymphoblastoid cells and skin.
- name: Loss of HSJ1 Co-chaperone Protein
  biological_scale: MOLECULAR
  role: molecular consequence of the lesion
  mechanism_confidence: ESTABLISHED
  description: >
    Absence of both HSJ1 isoforms: HSJ1a (277 aa, cytosolic and nuclear) and
    HSJ1b (324 aa, geranylgeranyl-anchored to the cytoplasmic face of the
    endoplasmic reticulum, the predominant isoform in neurons). Each carries an
    N-terminal J domain that binds HSP70 and stimulates its ATPase activity,
    and two C-terminal ubiquitin-interacting motifs that bind polyubiquitin
    chains and the proteasome. Loss of the protein therefore removes an
    HSP70 ATPase activator, an HSP70-binding client-delivery factor and a
    polyubiquitin-binding adaptor at once. Expression is highest in neurons,
    which fits the neural restriction of the disease.
  genes:
  - preferred_term: DNAJB2
    term:
      id: hgnc:5228
      label: DNAJB2
  molecular_functions:
  - preferred_term: HSJ1 J-domain stimulation of HSP70 ATPase activity
    term:
      id: GO:0001671
      label: ATPase activator activity
    modifier: ABSENT
  - preferred_term: HSJ1 J-domain binding to HSP70
    term:
      id: GO:0030544
      label: Hsp70 protein binding
    modifier: ABSENT
  - preferred_term: HSJ1 ubiquitin-interacting motif binding to polyubiquitylated clients
    term:
      id: GO:0031593
      label: polyubiquitin modification-dependent protein binding
    modifier: ABSENT
  - preferred_term: HSJ1 ubiquitin-interacting motif binding to the proteasome
    term:
      id: GO:0070628
      label: proteasome binding
    modifier: ABSENT
  evidence:
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "both isoforms have been shown to stimulate the ATPase activity of HSPA8 and to modulate its client binding"
    explanation: Grounds the ATPase activator activity and HSP70 client-binding role that patients lose.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "As a unique feature among human J proteins, the C-terminal region of DNAJB2 harbors two ubiquitin interaction motifs (UIMs) that mediate binding to polyubiquitylated proteins and to the proteasome"
    explanation: Grounds the polyubiquitin-binding and proteasome-binding functions.
  - reference: PMID:21625540
    reference_title: "Co-chaperone HSJ1a dually regulates the proteasomal degradation of ataxin-3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This dual regulation is dependent on the binding of the J-domain with HSP70, and the UIM domain with polyUb chains."
    explanation: Primary cell data showing the J domain binds HSP70 and the UIMs bind polyubiquitin chains.
  - reference: PMID:28031292
    reference_title: "Protein kinase CK2 modulates HSJ1 function through phosphorylation of the UIM2 domain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and facilitates their delivery to the proteasome for degradation."
    explanation: Restates the UIM-dependent polyubiquitin-binding and proteasome-delivery function of HSJ1.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "These mutations have been shown to lead to intron retention, premature termination, and severely reduced or lost DNAJB2 protein expression in patient fibroblast cultures"
    explanation: Summarises that the recurrent splice alleles abolish the protein in patient cells.
  - reference: PMID:22522442
    reference_title: "A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "HSJ1 is a neuronal enriched member of the HSP40/DNAJ co-chaperone family."
    explanation: Places the protein in the J-domain co-chaperone family and records its neuronal enrichment.
  downstream:
  - target: Impaired Ubiquitin-Proteasome Targeting of HSP70 Client Proteins
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred from HSJ1 function in overexpression and cell systems: HSJ1
      directs HSP70 clients to the proteasome rather than to refolding, so its
      absence is expected to slow client degradation. Impaired degradation has
      not been measured directly in patient neurons.
    evidence:
    - reference: PMID:32093037
      reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: "Instead of promoting the refolding of HSPA clients, DNAJB2 is considered to primarily direct them to degradation by the ubiquitin–proteasome system (UPS)"
      explanation: States the degradative function whose loss this edge infers.
  - target: Accumulation of Aggregation-Prone Client Proteins
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Separately from proteasomal targeting, HSJ1a keeps TDP-43 soluble by a
      J-domain-dependent, proteasome-independent route, so loss of HSJ1 is
      expected to remove anti-aggregation activity as well as degradative
      activity.
    evidence:
    - reference: PMID:26936937
      reference_title: "The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Using functionally deleted DNAJB2a constructs we demonstrated that TDP-43 clearance was J domain-dependent and was not affected by ubiquitin interacting motif deletion or proteasome inhibition."
      explanation: Shows an HSJ1a anti-aggregation activity toward TDP-43 independent of the proteasome; the disease edge is inferred from this gain-of-function experiment.
- name: Impaired Ubiquitin-Proteasome Targeting of HSP70 Client Proteins
  biological_scale: CELLULAR
  role: cellular consequence
  mechanism_confidence: PROVISIONAL
  description: >
    HSJ1 promotes ubiquitylation of HSP70-bound clients by STUB1 (CHIP),
    protects the chains from deubiquitylation and delivers the clients to the
    proteasome; HSJ1b additionally promotes ER-associated degradation of
    membrane and secretory proteins. In cell and animal systems,
    HSJ1 overexpression increases client ubiquitylation and degradation and
    lowers inclusion formation by polyglutamine proteins and mutant SOD1. The
    disease-relevant client proteins are not known, and impaired degradation
    has been inferred rather than measured in patient tissue.
  cell_types:
  - preferred_term: lower motor neuron
    term:
      id: CL:0008039
      label: lower motor neuron
  biological_processes:
  - preferred_term: proteasomal degradation of HSP70 client proteins
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: DECREASED
  - preferred_term: chaperone-mediated quality control of misfolded proteins
    term:
      id: GO:0006515
      label: protein quality control for misfolded or incompletely synthesized proteins
    modifier: DECREASED
  - preferred_term: HSJ1b-dependent ER-associated degradation
    term:
      id: GO:0036503
      label: ERAD pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:17426712
    reference_title: "Hsp40 molecules that target to the ubiquitin-proteasome system decrease inclusion formation in models of polyglutamine disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together these results show that HSJ1 proteins mediated an increase in target protein degradation via the ubiquitin-proteasome system (UPS)."
    explanation: Primary evidence that HSJ1 drives client degradation through the proteasome.
  - reference: PMID:17426712
    reference_title: "Hsp40 molecules that target to the ubiquitin-proteasome system decrease inclusion formation in models of polyglutamine disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, expression of HSJ1 proteins did not promote chaperone activity but caused an increase in ubiquitylation."
    explanation: Distinguishes the degradative from the refolding function of HSJ1.
  - reference: PMID:37070754
    reference_title: "Extension of the DNAJB2a isoform in a dominant neuromyopathy family."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "DNAJB2 interacts with polyubiquitinated proteins and the proteasome through its UIMs, and cooperates with STUB1 (CHIP) to promote client ubiquitination and sorting to UPS"
    explanation: Summarises the STUB1-dependent ubiquitylation and proteasomal sorting route.
  - reference: PMID:20395441
    reference_title: "DNAJB2 expression in normal and diseased human and mouse skeletal muscle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "DNAJB2 functions as an adaptor molecule for the evacuation and degradation of proteins through the ubiquitin-proteasome system"
    explanation: Background statement of the HSJ1 adaptor role in proteasomal degradation.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "to facilitate the proteasomal degradation of cystic fibrosis transmembrane conductance regulator (CFTR) through the ER-associated degradation (ERAD) pathway"
    explanation: Grounds the HSJ1b role in ER-associated degradation.
  - reference: PMID:24023695
    reference_title: "Molecular chaperone mediated late-stage neuroprotection in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In a cell model of SOD1(G93A) aggregation, HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1 aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner."
    explanation: Shows the combined J-domain and UIM dependence of HSJ1a client handling for a motor neuron disease protein.
  downstream:
  - target: Accumulation of Aggregation-Prone Client Proteins
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Clients not routed to degradation are expected to accumulate and
      aggregate; supported by gain-of-function experiments in which HSJ1
      lowers inclusion formation.
    evidence:
    - reference: PMID:22522442
      reference_title: "A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Overexpression of both HSJ1a and HSJ1b reduced inclusion formation induced by the mutated SOD1-A4V in a neuronal cellular model."
      explanation: Overexpression reduces inclusions in a neuronal model; the loss-of-function consequence is inferred.
- name: Accumulation of Aggregation-Prone Client Proteins
  biological_scale: CELLULAR
  role: cellular consequence
  mechanism_confidence: PROVISIONAL
  description: >
    In the one family studied, immunoblots of skin biopsies detected
    phospho-TDP-43 in two affected siblings (II.1 and II.2) and not in a single
    control; this shows the presence of the phosphorylated protein, not
    aggregates. Immunohistochemistry found phospho-alpha-synuclein deposits
    along dermal nerve fibres in one patient, the proband with Parkinson
    disease, while an affected sibling without parkinsonism was negative. These
    are the only patient-tissue observations bearing on protein accumulation;
    whether the same proteins accumulate in motor neurons is not known.
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with these data, we demonstrated TDP-43 accumulation in patients' skin but not in the control, supporting the hypothesis that in our patients the loss of DNAJB2 impairs the removal of toxic protein aggregates."
    explanation: Patient-tissue evidence of TDP-43 accumulation with loss of HSJ1.
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, IHC study of the proband's skin biopsy showed abnormal accumulation of p-alpha-syn along the nerve fiber, which was absent in the control"
    explanation: Phospho-alpha-synuclein accumulation in the patient with parkinsonism.
  - reference: PMID:26936937
    reference_title: "The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "To determine which chaperones were mediating TDP-43 clearance we over-expressed a range of heat shock proteins (HSPs) and identified DNAJB2a (encoded by DNAJB2, and also known as HSJ1a) as a potent anti-aggregation chaperone for TDP-43."
    explanation: Identifies TDP-43 as an HSJ1a client, which makes its accumulation in patient tissue mechanistically plausible.
  downstream:
  - target: Length-Dependent Degeneration of Lower Motor Neuron Axons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed but unproven: the authors attribute neuropathy to failed removal
      of toxic aggregates, yet HSJ1 loss in dermal axons was not accompanied by
      neurofilament impairment and the step from proteostatic failure to axon
      loss is unknown.
    evidence:
    - reference: PMID:35286755
      reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The mutation likely acts through a loss-of-function mechanism, leading to toxic protein aggregation such as TDP-43."
      explanation: The authors' causal proposal linking loss of HSJ1 to aggregation as the disease mechanism.
  - target: Length-Dependent Sensory Axon Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same unknown intermediates are presumed to account for the later
      involvement of sensory axons.
  - target: Nigrostriatal Dopaminergic Terminal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypothesised from phospho-alpha-synuclein deposits in the one patient with
      Parkinson disease in whom skin was examined; the link is not established.
- name: Length-Dependent Degeneration of Lower Motor Neuron Axons
  biological_scale: TISSUE
  role: core tissue lesion
  mechanism_confidence: ESTABLISHED
  description: >
    Degeneration of lower motor neurons and their long axons, affecting the
    longest lower-limb motor axons first. The founding family had a pure lower
    motor neuron disease; nerve conduction shows a motor axonal pattern, and
    needle EMG shows chronic denervation with very large motor unit potentials.
    No spinal cord pathology from a patient has been reported, so the relative
    contributions of cell body and axon are not established.
  cell_types:
  - preferred_term: lower motor neuron
    term:
      id: CL:0008039
      label: lower motor neuron
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  locations:
  - preferred_term: ventral horn of spinal cord
    term:
      id: UBERON:0002257
      label: ventral horn of spinal cord
  evidence:
  - reference: PMID:22522442
    reference_title: "A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons."
    explanation: Establishes the lower motor neuron as the primary target in the founding family.
  - reference: PMID:27449489
    reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electromyography (EMG) and nerve conduction testing revealed an active chronic motor neuron axonal disorder with huge motor unit action potentials (MUAPs) compatible with a SMA."
    explanation: Electrophysiological evidence of chronic lower motor neuron and axon loss.
  downstream:
  - target: Chronic Neurogenic Denervation of Distal Limb Muscle
    causal_link_type: DIRECT
    description: >-
      Loss of motor axons denervates the muscles they supply, beginning in the
      distal leg.
    evidence:
    - reference: PMID:27449489
      reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Electromyography (EMG) and nerve conduction testing revealed an active chronic motor neuron axonal disorder with huge motor unit action potentials (MUAPs) compatible with a SMA."
      explanation: Giant motor units are the electrophysiological signature of chronic denervation and reinnervation following motor axon loss.
  - target: Motor axonal neuropathy
    causal_link_type: DIRECT
    description: Motor axon loss is what the nerve conduction finding measures.
  - target: Peripheral axonal neuropathy
    causal_link_type: DIRECT
    description: >-
      Motor axon loss is the motor half of the length-dependent axonal motor
      and sensory polyneuropathy recorded on nerve conduction in the CMT2
      presentation.
  - target: Absent Achilles reflex
    causal_link_type: DIRECT
    description: >-
      Loss of the longest motor axons interrupts the efferent limb of the ankle
      stretch reflex first, consistent with the length-dependent pattern.
  - target: Hyporeflexia
    causal_link_type: DIRECT
    description: >-
      More widespread motor axon loss diminishes tendon reflexes beyond the
      ankle.
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Bulbar involvement is reported mainly at an advanced stage; bulbar motor
      neuron involvement is the presumed route, but no bulbar pathology or
      electrophysiology has been reported in this disease.
  - target: Respiratory insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Respiratory involvement is reported only at an advanced stage, alongside
      bulbar symptoms; extension of motor neuron loss to respiratory muscles is
      the presumed route, and the intermediates are not documented.
- name: Length-Dependent Sensory Axon Loss
  biological_scale: TISSUE
  role: secondary tissue lesion
  mechanism_confidence: ESTABLISHED
  description: >
    Loss of large-calibre sensory fibres, typically appearing later than the
    motor deficit and converting a dHMN presentation into axonal CMT2. Sural
    nerve biopsy in one patient showed reduced fibre density, mainly of large
    fibres, with acute axonal degeneration and rare regeneration clusters.
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sural nerve biopsy in patient II.1, at the age of 36 years, disclosed a moderate reduction of nerve fiber density, mainly involving the large-caliber fibers."
    explanation: Direct histological evidence of sensory nerve fibre loss.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Sensory symptoms such as decreased sensation appear with age in many if not all patients"
    explanation: Records the age-dependent emergence of sensory involvement across reported families.
  downstream:
  - target: Distal sensory impairment
    causal_link_type: DIRECT
    description: Sensory axon loss produces the distal sensory deficit.
  - target: Peripheral axonal neuropathy
    causal_link_type: DIRECT
    description: >-
      Sensory axon loss added to the motor deficit is what turns the dHMN
      picture into the axonal motor and sensory polyneuropathy of CMT2.
  - target: Absent Achilles reflex
    causal_link_type: DIRECT
    description: >-
      Loss of large-calibre sensory fibres removes the afferent limb of the
      ankle stretch reflex.
  - target: Hyporeflexia
    causal_link_type: DIRECT
    description: >-
      Large-fibre sensory loss also contributes to the more widespread reduction
      in tendon reflexes.
- name: Chronic Neurogenic Denervation of Distal Limb Muscle
  biological_scale: TISSUE
  role: tissue consequence
  mechanism_confidence: ESTABLISHED
  description: >
    Denervation atrophy and fatty replacement of distal leg muscles, affecting
    anterior and posterior leg compartments more than the thigh, and later the
    proximal legs and hands.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the proband, muscle CT showed severe fatty replacement of both the anterior and posterior compartments of the leg more than the thigh muscles"
    explanation: Imaging evidence of distal-predominant muscle denervation change.
  downstream:
  - target: Distal lower limb muscle weakness
    causal_link_type: DIRECT
  - target: Distal lower limb amyotrophy
    causal_link_type: DIRECT
  - target: Proximal lower limb muscle weakness
    causal_link_type: DIRECT
  - target: Distal upper limb muscle weakness
    causal_link_type: DIRECT
  - target: Pes cavus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Foot deformity is attributed to the neuropathy; the authors of the cohort
      read pes cavus and scoliosis as reflecting its severity.
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Scoliosis is reported alongside pes cavus in the same series and is read
      the same way, as a consequence of the neuromuscular weakness rather than a
      primary skeletal defect; the intermediate steps are not described.
  - target: Gait disturbance
    causal_link_type: DIRECT
    description: >-
      Distal leg weakness from denervation is the source of the gait difficulty
      that is the usual presenting symptom.
  - target: Loss of ambulation
    causal_link_type: DIRECT
    description: >-
      Progressive denervation spreading from distal to proximal leg muscles
      leads to wheelchair dependence in severely affected patients.
- name: Nigrostriatal Dopaminergic Terminal Degeneration
  biological_scale: TISSUE
  role: branch lesion in a subset
  mechanism_confidence: PROVISIONAL
  description: >
    Presynaptic dopaminergic deficit on dopamine transporter imaging in the
    patients with parkinsonism, one with juvenile onset at 16 years and one with
    typical Parkinson disease at 50 years. Whether this is caused by DNAJB2 loss
    or is coincidental is debated, given the small number of cases.
  cell_types:
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while DaT-Scan disclosed a severe, bilateral but asymmetric reduction of tracer uptake indicative of presynaptic dopaminergic terminal degeneration"
    explanation: Imaging evidence of dopaminergic terminal loss in the proband with Parkinson disease.
  - reference: PMID:27449489
    reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dopamine transporter imaging (TRODAT SPECT scan) showed markedly decreased presynaptic dopamine activity in the striata, more severe on the right side (Fig. 1B)."
    explanation: Independent imaging evidence in the patient with juvenile parkinsonism.
  downstream:
  - target: Parkinsonism
    causal_link_type: DIRECT
phenotypes:
- category: Neurologic
  name: Distal lower limb muscle weakness
  diagnostic: true
  description: >
    Weakness beginning in the distal legs, the presenting feature in all
    reported cohorts, progressing to paralysis of foot and leg muscles in severe
    families.
  phenotype_term:
    preferred_term: Distal lower limb muscle weakness
    term:
      id: HP:0009053
      label: Distal lower limb muscle weakness
  evidence:
  - reference: PMID:22522442
    reference_title: "A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset."
    explanation: Lower-limb predominant paralysis in the founding family.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "which manifests as pareses, muscle weakness, and atrophy appearing first in distal lower limbs and progressing slowly to proximal lower limbs and arms"
    explanation: Synthesises the distal lower-limb onset across reported families.
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical examination showed mild-to-moderate distal paresis in the upper limbs, a severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles."
    explanation: Complete distal leg paralysis in an advanced family.
- category: Neurologic
  name: Distal lower limb amyotrophy
  description: >
    Wasting of the distal leg muscles accompanying the weakness, later extending
    to all four limbs with distal predominance.
  phenotype_term:
    preferred_term: Distal lower limb amyotrophy
    term:
      id: HP:0008944
      label: Distal lower limb amyotrophy
  evidence:
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "which manifests as pareses, muscle weakness, and atrophy appearing first in distal lower limbs and progressing slowly to proximal lower limbs and arms"
    explanation: Atrophy begins in the distal lower limbs.
  - reference: PMID:27449489
    reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had muscle atrophy of all four limbs, more marked distally, and diminished reflexes"
    explanation: Distal-predominant wasting in the deletion family.
- category: Neurologic
  name: Proximal lower limb muscle weakness
  description: >
    Slow spread of weakness from the distal to the proximal legs; thigh
    weakness can become severe.
  phenotype_term:
    preferred_term: Proximal lower limb muscle weakness
    term:
      id: HP:0008994
      label: Proximal lower limb muscle weakness
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease onset occurred in the second or third decade of life, with gait difficulty and progressive weakness in the lower limbs, first distally and then proximally."
    explanation: Documents the distal-to-proximal spread of leg weakness.
- category: Neurologic
  name: Distal upper limb muscle weakness
  description: >
    Hand weakness appears later than leg involvement and is usually milder.
  phenotype_term:
    preferred_term: Distal upper limb muscle weakness
    term:
      id: HP:0008959
      label: Distal upper limb muscle weakness
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical examination showed mild-to-moderate distal paresis in the upper limbs, a severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles."
    explanation: Distal upper limb paresis, milder than the leg involvement.
- category: Neurologic
  name: Gait disturbance
  description: Gait difficulty is the usual presenting symptom.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease onset occurred in the second or third decade of life, with gait difficulty and progressive weakness in the lower limbs, first distally and then proximally."
    explanation: Gait difficulty at onset.
- category: Neurologic
  name: Motor axonal neuropathy
  diagnostic: true
  description: >
    Nerve conduction studies show a length-dependent motor axonal pattern, which
    is pure motor in dHMN presentations; in the Syrian c.446-1G>A family four
    of five patients had a motor-only pattern.
  phenotype_term:
    preferred_term: Motor axonal neuropathy
    term:
      id: HP:0007002
      label: Motor axonal neuropathy
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the five patients with the DNAJB2 c.446-1G>A homozygous variant, four showed an axonal motor neuropathy on NCS, while one displayed an axonal motor and sensory neuropathy."
    explanation: Gives the proportion with a motor-only axonal pattern in one family.
- category: Neurologic
  name: Peripheral axonal neuropathy
  description: >
    The CMT2 presentation: a length-dependent axonal motor and sensory
    polyneuropathy, present from the outset in some families and developing
    with age from a dHMN picture in others.
  phenotype_term:
    preferred_term: Axonal sensorimotor polyneuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies showed an axonal motor and sensory length-dependent polyneuropathy."
    explanation: Sensorimotor axonal neuropathy in a CMT2 family.
  - reference: PMID:28018906
    reference_title: "Chaperonopathies: Spotlight on Hereditary Motor Neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The patients in Spain displayed a dHMN or CMT2 phenotype and, in some cases, initial clinical manifestations that were consistent with dHMN and that subsequently evolved to CMT2 (Frasquet et al., 2016)."
    explanation: Records the evolution of dHMN into CMT2 in founder-allele families.
- category: Neurologic
  name: Distal sensory impairment
  description: >
    Reduced joint position, vibration and superficial sensation in the distal
    legs, usually appearing with age.
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Joint position, vibration and superficial sensation were reduced in the lower limbs."
    explanation: Distal sensory loss on examination.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Sensory symptoms such as decreased sensation appear with age in many if not all patients"
    explanation: Sensory loss is common and age-dependent.
- category: Neurologic
  name: Absent Achilles reflex
  description: >
    Ankle reflexes were absent in all six patients of the Syrian and Iranian
    families and in all three affected siblings of the Italian family.
  phenotype_term:
    preferred_term: Absent Achilles reflex
    term:
      id: HP:0003438
      label: Absent Achilles reflex
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ankle | Absent | Absent | Absent | Absent | Absent | Absent"
    explanation: Table 1 row recording absent ankle reflexes in all six DNAJB2 patients.
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ankle deep tendon reflexes | Absent | Absent | Absent"
    explanation: Table 1 row recording absent ankle reflexes in all three affected siblings.
- category: Neurologic
  name: Hyporeflexia
  description: >
    Tendon reflexes are diminished more widely, including in the upper limbs,
    with complete loss at the ankles and in some patients at the knees.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:27449489
    reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had muscle atrophy of all four limbs, more marked distally, and diminished reflexes"
    explanation: Diminished reflexes in the two siblings with axonal sensorimotor neuropathy.
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biceps | Diminished | Diminished | Diminished | Diminished | Diminished | Absent"
    explanation: Table 1 row showing diminished or absent biceps reflexes in all six patients.
- category: Musculoskeletal
  name: Pes cavus
  description: Present in all six patients of a recent two-family series.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All six patients had pes cavus; five had scoliosis (P2-6)."
    explanation: Pes cavus in 6 of 6 patients.
- category: Musculoskeletal
  name: Scoliosis
  description: Present in five of six patients of a recent two-family series.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All six patients had pes cavus; five had scoliosis (P2-6)."
    explanation: Scoliosis in 5 of 6 patients.
- category: Neurologic
  name: Dysphagia
  description: >
    Bulbar involvement with dysphagia, usually at an advanced stage but mild
    and earlier in two patients of the Syrian family.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bulbar dysfunction with mild dysphagia was present in two patients (P2, P3)."
    explanation: Bulbar dysphagia in two patients.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Bulbar and respiratory symptoms may develop at the advanced stage"
    explanation: Bulbar involvement is a late feature.
- category: Respiratory
  name: Respiratory insufficiency
  description: >
    Respiratory involvement may develop at advanced stages, alongside bulbar
    symptoms.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Bulbar and respiratory symptoms may develop at the advanced stage"
    explanation: Review-level statement that respiratory symptoms are a late feature.
- category: Neurologic
  name: Loss of ambulation
  description: >
    Wheelchair dependence from the fifth to sixth decade in a severely affected
    family; one of six patients was wheelchair-bound in another series.
  phenotype_term:
    preferred_term: Loss of ambulation
    term:
      id: HP:0002505
      label: Loss of ambulation
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients were wheelchair-bound from their fifth to sixth decade of life."
    explanation: Loss of ambulation in all affected members of one family.
- category: Neurologic
  name: Parkinsonism
  description: >
    Early-onset parkinsonism with presynaptic dopaminergic deficit in a few
    patients from different families: juvenile onset at 16 years with resting
    tremor and rigidity that responded only slightly and transiently to
    levodopa (deletion family), typical levodopa-responsive Parkinson disease at
    50 years (Italian frameshift family), and young-onset Parkinson disease in
    the fourth decade in a compound heterozygote. Whether the CNS features are
    part of the disease is considered unresolved because of the small numbers.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:27449489
    reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who at the age of 16 presented with a coarse resting tremor and rigidity, which gradually progressed"
    explanation: Juvenile parkinsonism in the deletion family.
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband developed typical PD at the age of 50 years, with asymmetric resting tremor, rigidity and hypokinesia responsive to L-DOPA treatment."
    explanation: Later-onset Parkinson disease in the frameshift family.
  - reference: PMID:41799927
    reference_title: "Co-Existing Charcot-Marie-Tooth Disease Type II and Parkinson's Disease Linked to a Novel DNAjB2 Pathogenic Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a 36-year-old female patient initially diagnosed with CMT2 at the age of 28, who later developed symptoms of PD in her fourth decade."
    explanation: Young-onset Parkinson disease after CMT2 in a compound heterozygote.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Early-onset parkinsonism has been reported in a few patients from different families"
    explanation: Review-level synthesis of parkinsonism across families.
- category: Neurologic
  name: Postural tremor
  description: >
    Mild postural tremor in two of six patients of one series, neither of whom
    had a full parkinsonian phenotype.
  phenotype_term:
    preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild postural tremor was observed in two patients (P5, P6)."
    explanation: Postural tremor in 2 of 6 DNAJB2 patients.
- category: Neurologic
  name: Sensorineural hearing impairment
  description: >
    Severe sensorineural deafness beginning in the third or fourth decade in all
    three affected siblings of one Italian family, and mild hearing loss in one
    patient of another series. An auditory-nerve mechanism is hypothesised, not
    shown.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, all patients had deafness, starting in the third or fourth decade of life."
    explanation: Deafness in all affected members of one family.
- category: Neurologic
  name: Restless legs
  description: >
    Restless legs syndrome in four of five assessed patients of one family; the
    finding comes from a single small series.
  phenotype_term:
    preferred_term: Restless legs
    term:
      id: HP:0012452
      label: Restless legs
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "restless legs syndrome was observed in four patients with a DNAJB2 variant but in none with a HINT1"
    explanation: Restless legs in four DNAJB2 patients.
- category: Musculoskeletal
  name: Rimmed vacuoles
  description: >
    Rimmed-vacuolar myopathy alongside neurogenic change on muscle biopsy in a
    single patient homozygous for c.184C>T.
  phenotype_term:
    preferred_term: Rimmed vacuolar myopathy
    term:
      id: HP:0003805
      label: Rimmed vacuoles
  evidence:
  - reference: PMID:37070754
    reference_title: "Extension of the DNAJB2a isoform in a dominant neuromyopathy family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Recently, rimmed-vacuolar myopathy in combination with dHMN was described in a patient homozygous for a DNAJB2 missense mutation"
    explanation: States the rimmed-vacuolar finding in a recessive DNAJB2 patient.
  - reference: PMID:35652544
    reference_title: "DNAJB2 c.184C>T mutation associated with distal hereditary motor neuropathy with rimmed vacuolar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a dHMN patient due to a homozygous c.184C>T variant in the DNAJB2 gene with rare neuropathic and myopathic characteristics on pathological examination."
    explanation: The primary case report of combined neuropathic and myopathic pathology.
genetic:
- name: DNAJB2
  gene_term:
    preferred_term: DNAJB2
    term:
      id: hgnc:5228
      label: DNAJB2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Biallelic loss-of-function variants in DNAJB2 are the only established
    cause. In a Spanish dHMN cohort DNAJB2 was the fourth most frequent cause,
    accounting for 6.7% of patients.
  evidence:
  - reference: PMID:25274842
    reference_title: "HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population."
    explanation: Segregation evidence in two further families.
  - reference: PMID:25274842
    reference_title: "HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2"
    explanation: Cohort-level confirmation of the gene-disease relationship.
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease."
    explanation: Segregation of a null allele in a third independent family.
  - reference: PMID:33369814
    reference_title: "Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes."
    explanation: Gives the share of dHMN attributable to DNAJB2 in a Spanish cohort.
  - reference: PMID:32298515
    reference_title: "Molecular analysis and clinical diversity of distal hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with a dHMN-plus phenotype (distal motor neuropathy and additional neurological deficits) carried variants in genes related to hereditary spastic paraplegia, amyotrophic lateral sclerosis and spinal muscular atrophy (FUS, KIF5A, KIF1B, ZFYVE26, DNAJB2)."
    explanation: Independent Chinese cohort placing DNAJB2 among genes of dHMN with additional neurological deficits.
  variants:
  - name: NM_006736.6:c.352+1G>A
    description: >
      Splice-donor variant reported homozygous in the founding Moroccan Jewish
      family and in Spanish families, where haplotype analysis showed a shared
      founder haplotype; also reported in a Brazilian family and, in compound
      heterozygosity, in a patient with CMT2 and young-onset Parkinson disease.
      It causes intron retention and severely reduced protein in patient
      fibroblasts.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DNAJB2
      term:
        id: hgnc:5228
        label: DNAJB2
    evidence:
    - reference: PMID:32093037
      reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "who identified a homozygous c.352+1G>A splice donor site mutation in a family with dHMN"
      explanation: The sentence, which in the review continues the attribution to Blumen and colleagues, names the splice-donor allele of the first reported dHMN family.
    - reference: PMID:28018906
      reference_title: "Chaperonopathies: Spotlight on Hereditary Motor Neuropathies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Hence, the DNAJB2 c.352+1G>A mutation appears to be a founder event (Lupo et al., 2016), and it is shared with a family reported elsewhere (Blumen et al., 2012)."
      explanation: Establishes the founder status of the allele.
    - reference: PMID:26752306
      reference_title: "Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event."
      explanation: Primary haplotype evidence for the founder allele in five Spanish families.
  - name: NM_006736.6:c.229+1G>A
    description: >
      Homozygous splice-donor variant in a dHMN family causing retention of
      intron 4, a premature stop codon and loss of protein.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DNAJB2
      term:
        id: hgnc:5228
        label: DNAJB2
    evidence:
    - reference: PMID:25274842
      reference_title: "HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A"
      explanation: Phenotype and zygosity of the allele in the reported family.
    - reference: PMID:25274842
      reference_title: "HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression"
      explanation: Patient fibroblast RNA and protein result establishing the molecular consequence.
  - name: NM_006736.6:c.145del p.(Val49TrpfsTer25)
    description: >
      Homozygous single-nucleotide deletion (reported as c.145delG) in the J
      domain, causing a frameshift and absent protein in an Italian CMT2 family
      with deafness and parkinsonism.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DNAJB2
      term:
        id: hgnc:5228
        label: DNAJB2
    evidence:
    - reference: PMID:35286755
      reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The CMT gene panel analysis in the proband (II.2) revealed the novel homozygous pathogenic variant c.145delG in the DNAJB2 gene (NM_006736.6), resulting in the frameshift p. Val49TrpfsTer25."
      explanation: Identifies the allele and its consequence.
  - name: 3.8 kb deletion of the 5' DNAJB2 exons
    description: >
      Homozygous ~3.8 kb deletion removing the first coding exons, which encode
      the J domain, found by whole-genome sequencing in a consanguineous family
      with SMA-like distal motor neuropathy, axonal sensorimotor neuropathy in
      two siblings and juvenile parkinsonism in one. It most likely abolishes
      expression; it also overlaps a predicted TUBA4A isoform.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DNAJB2
      term:
        id: hgnc:5228
        label: DNAJB2
    evidence:
    - reference: PMID:27449489
      reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "After performing homozygosity mapping and whole genome sequencing, we identified a 3.8 kb deletion, spanning the entire DnaJ domain of the HSJ1 protein, as the disease-segregating mutation."
      explanation: Identifies the structural allele and its segregation.
    - reference: PMID:32093037
      reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Moreover, the deletion also affects a predicted isoform of the TUBA4A gene, mutations in which are associated with ALS"
      explanation: Records the overlap with TUBA4A as a possible contributor to the phenotype.
  notes: >-
    Missense alleles are rare: c.14A>G p.(Tyr5Cys) in the J domain was reported
    homozygous in a CMT2 family (labelled CMT2T in the original report), with
    a phenotype comparable to the null alleles but no functional data; a
    homozygous c.184C>T variant was reported with dHMN and rimmed-vacuolar
    myopathy. Two variants were deliberately not curated as alleles of this
    disease. A heterozygous c.823+6C>T variant in an adult with severe
    sensorimotor polyneuropathy (PMID:40423229) was studied in fibroblasts but
    is a single heterozygous allele in a recessive gene. A dominant stop-loss
    variant, c.832T>G p.(*278Glyext*83), extends the HSJ1a isoform and causes a
    late-onset neuromyopathy with a dominant-negative mechanism in one German
    family (PMID:37070754); it is a distinct allelic disorder rather than this
    recessive loss-of-function disease.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Both alleles must be inactivated; most patients are homozygous and several
    families are consanguineous. Heterozygous carriers with about 40% of normal
    protein were clinically unaffected in the Italian family.
  evidence:
  - reference: PMID:22522442
    reference_title: "A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco."
    explanation: Recessive inheritance in the founding family.
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistently, WB analysis showed an absence of DNAJB2 protein in the homozygous patient and a significant reduction of protein level in the heterozygous carrier (40% of the control's protein level; Figure 3a–b)."
    explanation: Quantifies protein in an unaffected heterozygous carrier, consistent with recessive loss of function.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence has been published. A 2026 systematic review
    counted 46 reported families carrying 25 distinct variants. That is a case
    count, not a prevalence.
  evidence:
  - reference: PMID:42806108
    reference_title: "Variable phenotypic manifestations of two splice-site variants in DNAJB2: insights from two families and a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state."
    explanation: Gives the number of reported families.
progression:
- phase: Adolescent to early adult onset
  age_range: late first to early fourth decade
  notes: >-
    Onset is typically in the second decade, with a reported range from the
    late first to the early fourth decade, usually with gait difficulty and
    distal leg weakness.
  evidence:
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The onset of symptoms is typically in the 2nd decade of life, and has been reported to range from the late 1st to early 4th decades"
    explanation: Age-of-onset range across reported families.
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients developed symptoms during late adolescence, with initial manifestation occurring in the lower limbs in all cases."
    explanation: Late-adolescent onset in the lower limbs in a recent series.
- phase: Slow progression with proximal and sensory spread
  age_range: second decade onward
  notes: >-
    Motor function declines slowly and continuously; in one family the MRC sum
    score fell by an average of 0.78 points per year over up to 10 years of
    follow-up. Weakness spreads to the proximal legs and the hands, sensory
    involvement appears, and severely affected patients become wheelchair-bound
    by the fifth to sixth decade, with bulbar involvement at advanced stages.
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over the observation period, motor function declined on average by 0.78 points per year (on MRC-SS scale)"
    explanation: The only quantitative natural-history estimate.
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients were wheelchair-bound from their fifth to sixth decade of life."
    explanation: Late-stage loss of ambulation in a severe family.
treatments:
- name: Physical Therapy and Rehabilitation
  therapeutic_modality: BEHAVIORAL
  description: >
    Supportive physiotherapy and rehabilitation for distal weakness and gait
    impairment. No disease-modifying therapy exists.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Distal lower limb muscle weakness
    term:
      id: HP:0009053
      label: Distal lower limb muscle weakness
  - preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  notes: >-
    Recorded as standard supportive management for a progressive distal motor
    neuropathy, not as an intervention evaluated in this disease; no
    DNAJB2-specific treatment study has been published, so it carries no
    evidence block.
- name: Ankle-Foot Orthosis for Distal Leg Weakness
  therapeutic_modality: DEVICE
  description: >
    Orthotic support for distal leg weakness. The device concept is carried as a
    qualifier because NCIT's Brace term is a medical device and cannot sit in
    the treatment_term slot.
  treatment_term:
    preferred_term: ankle-foot orthosis fitting
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: ankle-foot orthosis
        term:
          id: NCIT:C86054
          label: Brace
  target_phenotypes:
  - preferred_term: Distal lower limb muscle weakness
    term:
      id: HP:0009053
      label: Distal lower limb muscle weakness
  notes: >-
    Standard supportive management for distal leg weakness, not evaluated in
    this disease.
- name: Levodopa for Associated Parkinsonism
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Levodopa has been used for the parkinsonism seen in a minority of patients,
    with a good response in a patient with typical Parkinson disease at 50
    years and only a slight, transient response in a patient with juvenile
    parkinsonism.
  treatment_term:
    preferred_term: levodopa pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  target_phenotypes:
  - preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband developed typical PD at the age of 50 years, with asymmetric resting tremor, rigidity and hypokinesia responsive to L-DOPA treatment."
    explanation: Levodopa-responsive parkinsonism in one patient.
  - reference: PMID:27449489
    reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 1-year follow-up, his tremor no longer responded to levodopa treatment."
    explanation: Loss of levodopa response in the juvenile-onset patient.
- name: Genetic Counseling
  therapeutic_modality: OTHER
  description: >
    Counselling for an autosomal recessive condition in which consanguinity is
    common and a founder splice allele recurs in Moroccan Jewish and Spanish
    families. Heterozygous carriers are unaffected.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25274842
    reference_title: "HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population."
    explanation: Autosomal recessive segregation is the basis of the recurrence risk and carrier counselling.
diagnosis:
- name: Nerve conduction studies and needle electromyography
  description: >
    Nerve conduction shows a length-dependent axonal pattern, pure motor in dHMN
    presentations and sensorimotor in CMT2 presentations; needle EMG shows
    chronic denervation with very large motor unit potentials.
  diagnosis_term:
    preferred_term: nerve conduction studies
    term:
      id: NCIT:C88502
      label: Nerve Conduction Velocity Test
  evidence:
  - reference: PMID:27449489
    reference_title: "Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electromyography (EMG) and nerve conduction testing revealed an active chronic motor neuron axonal disorder with huge motor unit action potentials (MUAPs) compatible with a SMA."
    explanation: The electrodiagnostic finding that frames the disease as a distal SMA.
- name: Multigene neuropathy panel sequencing
  description: >
    The diagnosis is made by finding biallelic DNAJB2 variants, typically on a
    CMT/hereditary motor neuropathy gene panel or exome. In a Spanish cohort
    screened with a 56-gene panel, the c.352+1G>A founder allele was found in
    two index cases and then in three further families. The 3.8 kb deletion was
    found by whole-genome sequencing, so copy-number-aware analysis is needed
    when sequencing finds a single or no variant.
  diagnosis_term:
    preferred_term: multigene neuropathy panel
    term:
      id: NCIT:C198412
      label: Multi-gene Panel Sequencing
  evidence:
  - reference: PMID:26752306
    reference_title: "Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy."
    explanation: Describes the panel through which DNAJB2 patients were identified.
  - reference: PMID:26752306
    reference_title: "Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The DNAJB2 c.352+1G>A mutation was detected in two cases"
    explanation: Panel yield for DNAJB2 in the cohort.
differential_diagnoses:
- name: HINT1-related autosomal recessive axonal neuropathy with neuromyotonia
  description: >
    The other recessive axonal neuropathy that presents as CMT2 or dHMN with
    lower-limb onset.
  distinguishing_features:
  - >
    HINT1 neuropathy begins earlier (childhood or early adolescence) and has
    neuromyotonia as a hallmark; DNAJB2 patients start later but develop more
    severe neuropathy.
  evidence:
  - reference: PMID:41549766
    reference_title: "Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease onset was typically later in patients with DNAJB2 variants (late adolescence or early adulthood) compared to patients with HINT1 variants (childhood or early adolescence), yet patients with DNAJB2 variants more frequently developed severe neuropathy, as reflected by higher CMTNS scores."
    explanation: Direct clinical comparison of the two disorders.
- name: Perry syndrome (DCTN1)
  description: >
    Relevant when parkinsonism accompanies the neuropathy: DCTN1 causes both a
    distal motor neuropathy and Perry syndrome, which combines early-onset
    parkinsonism with TDP-43 proteinopathy.
  distinguishing_features:
  - >
    Perry syndrome adds depression or apathy and central hypoventilation.
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "It is characterized clinically by early-onset parkinsonism, depression/apathy and central hypoventilation, and pathologically by degeneration of dopaminergic neurons and TDP-43 proteinopathy"
    explanation: The authors' comparison of Perry syndrome with the DNAJB2 phenotype.
- name: MME-related Charcot-Marie-Tooth disease type 2T
  description: >
    A nomenclature hazard rather than a biological mimic. The homozygous
    DNAJB2 p.(Tyr5Cys) CMT2 family was labelled CMT2T, a designation now used
    for MME-related neuropathy, so a historical "CMT2T" citation must be checked
    for which gene it means.
  evidence:
  - reference: PMID:28018906
    reference_title: "Chaperonopathies: Spotlight on Hereditary Motor Neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Two additional homozygous mutations were later described in the DNAJB2 gene, c.229+1G>A and c.14A>G (p.Y5C), in a family diagnosed with dHMN (dHMN5) and another with CMT2 (CMT2T), respectively (Gess et al., 2014)."
    explanation: Shows the CMT2T label applied to a DNAJB2 family.
discussions:
- discussion_id: dnajb2_axon_loss_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which HSJ1 client proteins and which downstream process link loss of HSJ1
    to motor and sensory axon degeneration?
  attaches_to:
  - pathophysiology#Impaired Ubiquitin-Proteasome Targeting of HSP70 Client Proteins
  - pathophysiology#Accumulation of Aggregation-Prone Client Proteins
  - pathophysiology#Length-Dependent Degeneration of Lower Motor Neuron Axons
  rationale: >
    Every functional study of HSJ1 is an overexpression or construct experiment
    in non-neuronal or cultured neuronal cells, and the only patient tissue
    examined is skin, lymphoblastoid cells and fibroblasts. Phospho-TDP-43 in
    patient skin is the one direct link to a client protein, but loss of HSJ1
    from dermal axons was not accompanied by neurofilament impairment. The
    review literature leaves open whether the lesion is proteotoxic or a defect
    of HSJ1b-dependent trafficking and secretion. No patient-derived motor
    neuron model or Dnajb2-null animal phenotype has been reported.
  evidence:
  - reference: PMID:35286755
    reference_title: "DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with these data, skin biopsy analysis showed a complete loss of DNAJB2 expression in patients that was not associated with an impairment of NF, leaving the pathomechanism of the axonal loss still unclear."
    explanation: The authors state the gap directly.
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The client protein(s) and processes relevant for the disease remain to be established: the pathomechanism could be envisioned to depend on cytotoxicity due to impaired protein quality control and turnover or a specific defect in protein trafficking or secretion caused by loss of DNAJB2b."
    explanation: Names the two competing mechanistic hypotheses.
- discussion_id: dnajb2_cns_features_attribution
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Are parkinsonism and other CNS features part of DNAJB2-related disease, or
    coincidental in a few families?
  attaches_to:
  - pathophysiology#Nigrostriatal Dopaminergic Terminal Degeneration
  - phenotypes#Parkinsonism
  rationale: >
    Parkinsonism with presynaptic dopaminergic deficit has now been reported
    in patients from several unrelated families with different alleles,
    including a compound heterozygote, and phospho-alpha-synuclein deposits
    were found in skin nerves of the patient with Parkinson disease but not in
    an affected sibling without parkinsonism. Against this, the numbers are very small, the deletion family's
    allele also overlaps a TUBA4A isoform, and the review literature considers
    the attribution unresolved.
  evidence:
  - reference: PMID:32093037
    reference_title: "Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Due to the small number of cases, it remains unclear whether the CNS symptoms in these patients are indeed due to the DNAJB2 mutations or additional factors"
    explanation: States the uncertainty.
  - reference: PMID:41799927
    reference_title: "Co-Existing Charcot-Marie-Tooth Disease Type II and Parkinson's Disease Linked to a Novel DNAjB2 Pathogenic Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, this is the first case report describing the dual phenotype of CMT2 and young-onset PD linked to compound heterozygosity in DNAjB2."
    explanation: An additional unrelated patient with the dual phenotype.
notes: >-
  The dHMN and CMT2 presentations are curated as one disease rather than as
  subtypes: the same alleles produce both, MONDO lists DNAJB2-related CMT2 as an
  exact synonym of this term, and patients diagnosed with dHMN can evolve into
  CMT2. No GeneReviews chapter covers this disease. PMID:27083531 (Frasquet et
  al. 2016) has no available abstract text and is listed without evidence
  items. The 2026 series of two DNAJB2 families also
  reported depression in all assessed patients, fatigue in most and reduced
  quality of life, but its authors note that the patients were refugees and
  that migration stressors may contribute, so those features are not curated
  as disease phenotypes. Four phenotypes are deliberately left without an
  incoming causal edge: sensorineural hearing impairment (an auditory-nerve
  mechanism is hypothesised by the reporting authors but not shown), restless
  legs syndrome and postural tremor (each reported in a single small series
  with no mechanism proposed), and rimmed vacuoles (a myopathic biopsy finding
  in a single patient, whose relation to HSJ1 loss is not established).
📚

References & Deep Research

References

11
PMID:22522442
A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation.
No top-level findings curated for this source.
PMID:25274842
HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum.
No top-level findings curated for this source.
PMID:27449489
Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism.
No top-level findings curated for this source.
PMID:35286755
DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening.
No top-level findings curated for this source.
PMID:41549766
Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease.
No top-level findings curated for this source.
PMID:42806108
Variable phenotypic manifestations of two splice-site variants in DNAJB2: insights from two families and a systematic review.
No top-level findings curated for this source.
PMID:32093037
Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results.
No top-level findings curated for this source.
PMID:28018906
Chaperonopathies: Spotlight on Hereditary Motor Neuropathies.
No top-level findings curated for this source.
PMID:37070754
Extension of the DNAJB2a isoform in a dominant neuromyopathy family.
No top-level findings curated for this source.
PMID:26752306
Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.
No top-level findings curated for this source.
PMID:27083531
Phenotype and natural history of inherited neuropathies caused by HSJ1 c.352+1G>A mutation.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Review round: wire disconnected phenotypes into the pathograph · 2026-10-04T02:33:42Z · View source

Addressed the 2026-10-01 review item 1. Added downstream edges: motor and sensory axon-loss nodes to Peripheral axonal neuropathy, Absent Achilles reflex and Hyporeflexia (efferent and afferent limbs of the stretch reflex); motor neuron degeneration to Dysphagia and Respiratory insufficiency as INDIRECT_UNKNOWN_INTERMEDIATES, described as advanced-stage features with no bulbar pathology reported; denervation to Gait disturbance and Loss of ambulation (DIRECT) and Scoliosis (INDIRECT_UNKNOWN_INTERMEDIATES, read with pes cavus as in PMID:41549766). Connected phenotypes went from 8/20 to 16/20. The entry notes now say why hearing impairment, restless legs, postural tremor and rimmed vacuoles stay unwired. PMID:28182921 kept because the committed deep-research report cites it. Added the missing MONDO:0013947 diseaseterm enum cache row written by just validate.

Review round 1: Neuronopathy_Distal_Hereditary_Motor_Autosomal_Recessive_5 · 2026-10-01T15:38:20Z · View source

Applied independent review of the initial commit. Added Absent Achilles reflex (HP:0003438; chosen over HP:0001284 Areflexia because the sources report absence specifically at the ankle, 6/6 in PMID:41549766 Table 1 and 3/3 in PMID:35286755 Table 1) and Hyporeflexia (HP:0001265; generalized diminished reflexes, PMID:27449489 and PMID:41549766 biceps row). Added diagnosis section: nerve conduction (NCIT:C88502) and multi-gene panel sequencing (NCIT:C198412), both verified via OLS. Cited previously uncited caches: PMID:26752306 (panel and primary founder-haplotype evidence on c.352+1G>A), PMID:32298515 (Chinese dHMN-plus cohort), PMID:28031292 and PMID:20395441 (background HSJ1 UIM/UPS function). PMID:28182921 kept uncited in the entry because the DR report cites it; it is a duplicate PubMed record of PMID:17426712. Prevalence class changed to ULTRA_RARE with CASES_IN_LITERATURE (permitted by the enum description). Genetic counseling evidence replaced with the Gess 2014 cosegregation sentence. Synonyms: dropped HSJ1-related hereditary neuropathy and the stub-only 'spinal muscular atrophy, distal, autosomal recessive, 5' (not in the MONDO record via runoak); added MONDO's BROAD synonyms young adult-onset distal hereditary motor neuropathy and Young adult-onset dHMN. Rewrote notes to remove process narration. Aggregation node description now states the phospho-TDP-43 immunoblot was in two siblings versus one control and shows presence not aggregates, and that p-alpha-syn was positive in the proband only; PMID:26936937 overexpression item marked directness INDIRECT. Optional items taken: postural tremor (2/6), respiratory insufficiency (review snippet); the Gess c.229+1G>A variant item split into a HUMAN_CLINICAL phenotype/zygosity clause and an IN_VITRO RNA/protein clause. Not taken: VERY_FREQUENT on distal lower-limb weakness (no snippet states a distal-specific frequency) and new phenotype edges (no source states the mechanism of areflexia or tremor).

Create: Neuronopathy_Distal_Hereditary_Motor_Autosomal_Recessive_5 · 2026-10-01T15:23:47Z · View source

Created the DNAJB2/HSJ1 entry for MONDO:0013947 from the stub. Deep research: requested falcon via just dr_fallback='--fallback' research-disorder; falcon was not configured (no EDISON_API_KEY), so claude_code produced the report (research/Neuronopathy_Distal_Hereditary_Motor_Autosomal_Recessive_5-deep-research-claude_code.md; frontmatter fell_back: true, requested_provider: falcon; no citations sidecar was written). Reference validation 22/22 resolved, 0 off topic; term validation 27/28 resolved, 0 mislabelled. just preflight-dr returned PASS (DNAJB2 mentioned 39 times, OMIM 614881 matches). All cited PMIDs fetched and read; PMID:27083531 (Frasquet 2016) cached with content_type unavailable after a --force retry, so it is listed in references but not used as evidence. Structure: 8-node causal chain from biallelic DNAJB2 LoF to loss of HSJ1 (molecular_functions GO:0001671 ATPase activator activity, GO:0030544 Hsp70 protein binding, GO:0031593 polyubiquitin modification-dependent protein binding, GO:0070628 proteasome binding, all ABSENT, grounded in the Sarparanta 2020 review and HSJ1a ataxin-3 cell data PMID:21625540) to impaired UPS client targeting and aggregate accumulation (edges INDIRECT_UNKNOWN_INTERMEDIATES, gain-of-function cell evidence marked directness INDIRECT), lower motor neuron axon degeneration, sensory axon loss, denervation and a provisional nigrostriatal branch. 16 phenotypes; 4 variants (c.352+1G>A founder, c.229+1G>A, c.145delG, 3.8 kb deletion). Key decisions: dHMN and CMT2 presentations curated as one disease rather than subtypes (MONDO lists DNAJB2-related CMT2 as an exact synonym; dHMN evolves into CMT2); the dominant DNAJB2a stop-loss neuromyopathy (PMID:37070754) and a heterozygous c.823+6C>T case (PMID:40423229) recorded in genetic notes only; depression/fatigue from the 2026 refugee cohort not curated as phenotypes because the authors flag migration stress as a confounder; historical CMT2T label for the p.Tyr5Cys family recorded as a nomenclature differential. No GeneReviews chapter (check-genereviews --online NO_CHAPTER). Validation: just validate 0 issues (83/83 snippets), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms (incl. --resolve), gene-activity grounding vs origin/main, check-snippet-length, check-title-snippets, check-snippet-grading (after aligning one duplicated Gess 2014 quote to IN_VITRO), check-folded-hyphens, check-coarse-phenotypes, check-term-cache-integrity and check-cache-order all OK.

Claude Code ▸
Research report: Neuronopathy, distal hereditary motor, autosomal recessive 5 (DNAJB2-related dHMN / AR-CMT2)
claude-haiku-4-5-20251001, claude-opus-5-5 2026-10-01T10:55:01.646058

Checking the cached reference titles for the DNAJB2 papers already in the repo.

The CMT2T entry turned out to be MME, not DNAJB2, so I'm now searching the literature for the DNAJB2 primary papers.

Fetching the primary DNAJB2 abstracts from PubMed so the report can quote them exactly.

The fetch tool paraphrases abstracts, so I'll cache them with the repo's own reference fetcher to get verbatim text.

Progress: I've confirmed the core literature (Blumen 2012, Saveri 2022, Sarparanta 2020 review). Next I'm resolving PMIDs for the follow-up case series (Gess, Frasquet, Sanchez).

Almost done gathering; checking variant details in the 2026 German cohort and the identifiers in the local MONDO cache before writing.

Research report: Neuronopathy, distal hereditary motor, autosomal recessive 5 (DNAJB2-related dHMN / AR-CMT2)

MONDO: MONDO:0013947 · Category: Genetic (Mendelian, autosomal recessive) · Report date: 2026-10-01

Before you use this report

  • Snippets. Every quoted snippet below was copied from a references_cache/PMID_*.md file in this worktree, not from memory or a summarizer. To cache them I ran just fetch-reference for 22 PMIDs. That added uncommitted files under references_cache/. Commit the ones the entry ends up citing; the rest can be pruned.
  • Two references are not quotable:
  • PMID:27083531 (Frasquet 2016, natural history of c.352+1G>A) cached with content_type: unavailable, so it has no quotable text. Don't quote it until a retry succeeds.
  • PMID:38702287 (Tazir 2024 review) hit an NCBI rate limit (HTTP 429) and was not cached.
  • Identifiers I could not check from a source in this session: the OMIM phenotype number (614881), the DNAJB2 gene MIM (604139), and any Orphanet, ICD or MeSH codes. Look these up before binding them (CLAUDE.md: "Every CURIE is read from a source in the same step it is written"). MONDO:0013947 and its label are confirmed in cache/mondo/terms.csv. The draft's hgnc:5228 for DNAJB2 should be confirmed with just validate-terms.
  • Two issues in the existing draft:
  • The synonym "DNAJB2-related CMT2" is supported by the literature (several families present as CMT2).
  • The KB entry Charcot-Marie-Tooth_Disease_Axonal_Type_2T is MME, not DNAJB2. Don't use it as a sibling or template for this gene.

1. Disease information

Overview. HMNR5 is a rare autosomal recessive disease of the lower motor neurons and peripheral axons. It is caused by biallelic loss-of-function variants in DNAJB2 (also called HSJ1), which encodes a neuron-enriched HSP40/DNAJ co-chaperone of HSP70. - The first family (Moroccan Jewish, Blumen 2012) had a pure lower motor neuron distal hereditary motor neuropathy (dHMN): mostly lower-limb paralysis, starting in early adulthood. - Later families widened this into a dHMN ↔ axonal CMT2 continuum. Sensory involvement often appears with age. Some patients also have parkinsonism, hearing loss or a myopathy.

Key quotes: - PMID:22522442 (Blumen 2012, Ann Neurol): "We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco. The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset." - PMID:32093037 (Sarparanta 2020, review): "Recessive DNAJB2 mutations (Table 4) have been identified as a so far uncommon cause of peripheral neuropathies, which may present as distal hereditary motor neuropathy (dHMN) or sensory and motor neuropathy (Charcot–Marie–Tooth disease type 2, CMT2)"

Identifiers: - MONDO:0013947, label "neuronopathy, distal hereditary motor, autosomal recessive 5" (verified in the cache). - OMIM phenotype 614881 (HMNR5) and DNAJB2 gene MIM 604139: verify on OMIM. - Sanchez 2016 (PMID:27449489) writes "DNAJB2 (MIM# 614881)", which uses the phenotype number for the gene. Don't copy that.

Synonyms: dHMN5 (AR) / DSMA5 / distal spinal muscular atrophy, autosomal recessive 5 (Saveri uses "dSMA5‑AR"); HSJ1-related hereditary neuropathy; DNAJB2-related CMT2 (AR-CMT2).

Source type: Aggregated case reports and small family series. Per the 2026 systematic review, there are about 46 families worldwide. No registry or EHR data exist.

2. Etiology

  • Cause: biallelic germline DNAJB2 variants. Most patients are homozygous, often from consanguineous families.
  • PMID:42806108 (Ghermezcheshmeh 2026): "In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state."
  • Genetic risk:
  • A recurrent founder allele, c.352+1G>A, is shared by Spanish families and the Moroccan family.
  • PMID:28018906 (Lupo 2016 review): "Hence, the DNAJB2 c.352+1G>A mutation appears to be a founder event (Lupo et al., 2016), and it is shared with a family reported elsewhere (Blumen et al., 2012)."
  • Environmental, protective and gene–environment factors: none reported. No modifier gene is known.
  • Why only some patients develop parkinsonism is unexplained. Saveri (PMID:35286755) excluded PARK2/SNCA dosage changes and found no PD-panel variants in their PD case.
  • Heat or proteotoxic stress is a plausible modifier, but only from in vitro work (see §6).

3. Phenotypes

Frequencies are qualitative because the case series are small.

Phenotype Suggested HPO (verify) Onset / course Frequency Key evidence
Distal lower-limb weakness and atrophy, the first sign HP:0009053 Distal lower limb muscle weakness (already in the draft); HP:0007210 Lower limb amyotrophy 2nd–3rd decade; slowly progressive Nearly all PMID:32093037: "pareses, muscle weakness, and atrophy appearing first in distal lower limbs and progressing slowly to proximal lower limbs and arms"
Spread to proximal legs and arms HP:0008994 Proximal muscle weakness in lower limbs; HP:0008959 Distal upper limb muscle weakness Later Common Saveri: "progressive weakness in the lower limbs, first distally and then proximally"
Gait difficulty HP:0001288 Gait disturbance Presenting symptom Common Saveri Table 1 onset ages 28, 28, 15 with "Gait difficulty"
Late sensory loss (CMT2 conversion) HP:0003474 Somatic sensory dysfunction / HP:0010871 Sensory ataxia (rare) Appears with age "many if not all" PMID:32093037: "Sensory symptoms such as decreased sensation appear with age in many if not all patients"
Axonal motor (± sensory) neuropathy on nerve conduction HP:0007002 Motor axonal neuropathy; HP:0003477 Peripheral axonal neuropathy — All PMID:35286755: "Nerve conduction studies showed an axonal motor and sensory length-dependent polyneuropathy."
Pes cavus HP:0001761 — 6/6 in Bjelica PMID:41549766: "All six patients had pes cavus; five had scoliosis (P2‐6)."
Scoliosis HP:0002650 — 5/6 (Bjelica) same
Bulbar or respiratory involvement HP:0002015 Dysphagia; HP:0002093 Respiratory insufficiency Advanced stage Occasional PMID:32093037: "Bulbar and respiratory symptoms may develop at the advanced stage"
Wheelchair dependence HP:0002505 Loss of ambulation 5th–6th decade (Italian family) Variable Saveri: "All patients were wheelchair‐bound from their fifth to sixth decade of life."
Parkinsonism / young-onset PD (levodopa-responsive or partly responsive) HP:0001300 Parkinsonism Juvenile (16 y) to 50 y ~5 reported patients PMID:41799927 (Lerint 2026): "The association between clinical Parkinsonism and DNAjB2 variants has only been reported previously in 4 patients."
Sensorineural hearing loss HP:0000407 3rd–4th decade 3/3 in one Italian family; 1/6 Bjelica PMID:35286755: "All patients had severe hearing loss and the proband also had Parkinson's disease (PD)."
Rimmed-vacuolar myopathy on biopsy HP:0003805 Rimmed vacuoles (verify) — Single case PMID:35652544
Depression HP:0000716 — 6/6 in Bjelica PMID:41549766: "All patients with DNAJB2 variants fulfilled criteria for depression, compared with one with a HINT1 variant."
Fatigue HP:0012378 — Majority (Bjelica) same abstract
Postural tremor HP:0002174 — 2/6 (Bjelica) PMID:41549766
Frontotemporal atrophy with behavioural change; cerebellar ataxia — — Single patients; causal link uncertain PMID:32093037: "it remains unclear whether the CNS symptoms in these patients are indeed due to the DNAJB2 mutations or additional factors"

Quality of life. Bjelica 2026 (PMID:41549766) is the only study that measured it, using SCOPA-AUT, BDI, FSS and painDETECT. Non-motor symptoms (depression, fatigue, autonomic symptoms) reduced quality of life compared with controls.

4. Genetic and molecular information

  • Gene: DNAJB2 (HSJ1), chromosome 2q35 (mapped in Blumen to 2q34–q36.1). HGNC:5228 (check against cache/hgnc/terms.csv).
  • Protein: an N-terminal J domain, a G/F region, a Ser/Thr-rich region, and two ubiquitin-interacting motifs (UIMs). There are two isoforms:
  • HSJ1a/DNAJB2a: 277 aa, cytosolic and nuclear.
  • HSJ1b/DNAJB2b: 324 aa, anchored to the cytoplasmic face of the ER by a C-terminal geranylgeranyl group. This is the main isoform in neurons.
  • PMID:32093037: "As a unique feature among human J proteins, the C-terminal region of DNAJB2 harbors two ubiquitin interaction motifs (UIMs) that mediate binding to polyubiquitylated proteins and to the proteasome"

Reported pathogenic variants (all germline, mostly homozygous):

Variant (NM_006736) Type Phenotype Source
c.352+1G>A splice donor; Spanish/Moroccan founder dHMN/CMT2, YOPD PMID:22522442; 28018906; 41799927 (compound het with c.175+2T>A)
c.229+1G>A splice donor → intron 4 retention, protein lost dHMN PMID:25274842
c.14A>G p.Tyr5Cys missense in J domain CMT2 PMID:25274842
c.619-1G>A; c.310delC splice acceptor; frameshift dHMN/CMT2 cited in PMID:32093037
~3.8 kb deletion of exons 1–3/4 (+ upstream) structural, null SMA + juvenile parkinsonism PMID:27449489
c.145delG p.Val49TrpfsTer25 frameshift, null CMT2 + deafness + PD PMID:35286755
c.184C>T nonsense (verify protein change) dHMN + rimmed-vacuolar myopathy PMID:35652544
c.446-1G>A (also c.446-1G>C); c.445+1del (new) splice dHMN or CMT2 PMID:41549766; 42806108
c.99C>G p.Asp33Glu missense, VUS CMT2 PMID:41549766
c.175+2T>A splice CMT2 + YOPD (compound het) PMID:41799927

Key quotes: - PMID:25274842 (Gess 2014): "One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression." - Same paper: "we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2."

Functional consequence: loss of function, with no protein detected. - PMID:35286755: "DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy." - Saveri also found heterozygous carriers at 40% of normal protein and clinically unaffected, which supports a recessive, threshold-type mechanism.

Genotype–phenotype: PMID:42806108 found "marked clinical heterogeneity but not a significant genotype-phenotype correlation."

Population frequency: c.145delG and c.14A>G are absent from gnomAD (per the papers). Pull gnomAD frequencies for the founder allele directly; I did not retrieve them.

Separate entities to keep out of this entry: - A heterozygous c.823+6C>T VUS in an adult sensory-motor polyneuropathy (PMID:40423229, classified VUS). - A dominant DNAJB2a isoform-extension neuromyopathy (PMID:37070754).

Neither fits the HMNR5 recessive loss-of-function model. Record them as notes or exclusions, not as pathogenic variants for this disease.

Epigenetic and chromosomal findings: none reported, apart from the structural deletion above.

5. Environmental information

None reported: no environmental, lifestyle or infectious factors. The environmental: section would be empty; if a block is added, use a Left deliberately uncited. waiver.

6. Mechanism and pathophysiology

Causal chain (steps marked inferred are not directly shown in patient neurons):

  1. Biallelic DNAJB2 null or splice variants lead to intron retention, premature stop codons or deletion of the J domain. Both HSJ1a and HSJ1b are lost (shown in patient fibroblasts, lymphoblastoid cells and skin).
  2. PMID:22522442: "identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b."
  3. Loss of the HSJ1 co-chaperone removes J-domain stimulation of HSPA8/HSP70 ATPase activity. It also removes UIM-mediated handoff of ubiquitinated clients to the proteasome and STUB1/CHIP-assisted ubiquitination.
  4. PMID:32093037: "Instead of promoting the refolding of HSPA clients, DNAJB2 is considered to primarily direct them to degradation by the ubiquitin–proteasome system (UPS)"
  5. Protein quality control fails (ubiquitin–proteasome and ER-associated degradation via HSJ1b; inferred). This leads to accumulation and aggregation of misfolded clients such as TDP-43, mutant SOD1 and α-synuclein.
  6. PMID:35286755: "The mutation likely acts through a loss-of-function mechanism, leading to toxic protein aggregation such as TDP-43."
  7. Patient skin showed phospho-TDP-43. The patient with PD also had phospho-α-synuclein deposits in skin nerves.
  8. Branch A (main): motor neurons in the spinal cord anterior horn and their long axons degenerate (inferred; no patient spinal cord pathology has been reported). This produces length-dependent axonal loss, first in long lower-limb motor axons, and later in sensory axons (sural biopsy: loss of large fibres).
  9. PMID:22522442: "this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons."
  10. Denervation causes distal muscle atrophy and weakness, then pes cavus and scoliosis, then loss of ambulation. Occasionally there are secondary myopathic changes with rimmed vacuoles (PMID:35652544).
  11. Branch B: degeneration of dopaminergic nigrostriatal terminals (DaT-scan shows presynaptic deficit) in a subset, leading to parkinsonism.
  12. The Sanchez deletion study links HSJ1b loss to reduced BDNF and tau levels (HEK293 cells only).
  13. Branch C: auditory-nerve involvement causing sensorineural deafness. Saveri proposes this ("We hypothesize the same mechanism"); it is not demonstrated.
  14. Alternative or additional mechanism (hypothesis): loss of HSJ1b-dependent trafficking or secretion, such as Golgi clathrin-coated-vesicle sorting and BDNF secretion. PMID:32093037: "the pathomechanism could be envisioned to depend on cytotoxicity due to impaired protein quality control and turnover or a specific defect in protein trafficking or secretion caused by loss of DNAJB2b."
  15. Known gap (suits a KNOWLEDGE_GAP discussion): PMID:35286755: "skin biopsy analysis showed a complete loss of DNAJB2 expression in patients that was not associated with an impairment of NF, leaving the pathomechanism of the axonal loss still unclear."

Suggested GO terms (look each one up before binding): - protein folding chaperone / Hsp70 protein binding / ATPase activator activity (molecular function) - proteasome-mediated ubiquitin-dependent protein catabolic process - ERAD pathway - negative regulation of protein aggregation / protein refolding - response to heat (HSJ1 is heat-inducible; PMID:40423229) - neuron projection maintenance / axon degeneration

Suggested CL terms: lower motor neuron / spinal cord motor neuron; dopaminergic neuron (Branch B); sensory neuron; skeletal muscle fibre (secondary).

Suggested GO cellular component terms: cytosol, nucleus (HSJ1a); ER membrane, cytoplasmic side (HSJ1b); proteasome complex.

Suggested biological_scale tags: step 1 MOLECULAR; steps 2–3 CELLULAR; step 4 TISSUE; steps 5–6 ORGANISM.

Omics, single-cell and CRISPR data: none specific to HMNR5.

7. Anatomical structures

  • Primary: peripheral nervous system, specifically spinal motor neurons and their axons (UBERON: ventral horn of spinal cord; peripheral nerve; sciatic/peroneal nerve).
  • Secondary: distal leg muscles (anterior and posterior leg compartments more than thigh on CT, per Saveri), then the hands; foot (pes cavus); vertebral column (scoliosis).
  • Central nervous system in a subset: substantia nigra and striatal dopaminergic terminals; auditory nerve.
  • Laterality: bilateral and symmetric. The parkinsonism can be asymmetric.

8. Temporal development

  • Onset: usually the 2nd decade, with a reported range from the late 1st to early 4th decade (PMID:32093037). In Bjelica, onset was 17–21 y.
  • Pattern: insidious, starting with gait difficulty.
  • Progression: slow and continuous. The only quantitative natural history is PMID:41549766: "all patients with DNAJB2 variants experienced a progressive loss of motor function over a follow‐up period of up to 10 years, with an annual decline in the MRC‐SS score of 0.78 points per year."
  • Suggested phases for progression::
  • Pure distal motor (dHMN) phase.
  • Proximal and upper-limb spread with later sensory involvement (CMT2 phase).
  • Advanced phase: wheelchair use in the 5th–6th decade in severe families; possible bulbar or respiratory involvement.
  • Remission: none.

9. Inheritance and population

  • Inheritance: autosomal recessive (HP:0000007, verify). Penetrance appears complete in homozygotes. Expressivity varies (dHMN vs CMT2 ± parkinsonism or deafness, even within one family). Heterozygous carriers are unaffected (Saveri). There is no anticipation.
  • Consanguinity: frequent (Iranian, Syrian and Moroccan families).
  • Founder allele: c.352+1G>A in Spain and Morocco (Moroccan Jewish), and reported in Brazil.
  • Prevalence: no disease-specific estimate. Use prevalence_class: NOT_YET_DOCUMENTED or measure_type: CASES_IN_LITERATURE with "~46 families" (PMID:42806108).
  • Context — pooled hereditary motor neuropathy prevalence: PMID:36445400: "Their cumulative estimated prevalence is 2.14/100 000".
  • Share of dHMN caused by DNAJB2: in a European cohort, DNAJB2 explained 6.7% of genetically solved dHMN (PMID:33369814: "The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes.").
  • Sex ratio: no bias reported.

10. Diagnostics

  • Nerve conduction and EMG: reduced compound muscle action potentials with relatively preserved conduction velocities (axonal pattern). Sensory potentials are normal early (dHMN) and reduced later (CMT2). EMG shows chronic denervation.
  • Muscle imaging: CT/MRI shows fatty replacement of the leg more than the thigh.
  • Biopsy:
  • Sural nerve: loss of large myelinated fibres with acute axonal degeneration.
  • Muscle: neurogenic changes, with rimmed vacuoles in one case.
  • Skin: loss of DNAJB2 immunostaining in dermal axons, and phospho-TDP-43 and phospho-α-synuclein deposits. These are research findings, but skin DNAJB2 immunostaining could serve as a functional test of variant pathogenicity.
  • DaT-scan when parkinsonism is present. Audiometry and brainstem auditory evoked potentials — Saveri recommends DNAJB2 testing in CMT2 or dSMA with deafness.
  • Genetic testing: multigene neuropathy/dHMN panels or whole-exome sequencing. Copy-number or whole-genome analysis is needed to find the structural deletion (found by whole-genome sequencing in PMID:27449489). Splice variants can be confirmed with fibroblast or lymphoblastoid RNA/protein studies.
  • Diagnostic yield for dHMN is low overall: PMID:32298515 solved 24/70 (34.3%) and placed DNAJB2 among the "dHMN-plus" genes. Fernández-Eulate 2023 (PMID:37470033) reports non-5q SMA yield and is cached but I did not extract a DNAJB2 figure.
  • Differential diagnosis:
  • Other recessive dHMN/CMT2 genes: HINT1 (earlier, childhood onset, neuromyotonia; PMID:41549766), SIGMAR1, IGHMBP2, MME (later onset).
  • Dominant dHMN genes: HSPB1, HSPB8, GARS1, BICD2.
  • 5q SMA (exclude by SMN1 testing), ALS (no upper motor neuron signs here), and Perry syndrome / DCTN1 when parkinsonism is present.
  • Screening: carrier or cascade testing within families. There is no newborn screening.

11. Outcome and prognosis

  • Survival: no data. Life expectancy is presumed near-normal in pure dHMN; this is not documented.
  • Morbidity: progressive motor disability, with wheelchair dependence in severe families by the 5th–6th decade. Disease severity on CMTESv2 was 17–20 (moderate to severe) in Saveri.
  • Complications: bulbar or respiratory involvement late; deafness; parkinsonism; depression; fatigue.
  • No recovery is expected. No prognostic biomarkers are known. Parkinsonism and deafness appear to mark a more severe course, based on very few cases.

12. Treatment

There is no disease-modifying therapy and no registered DNAJB2-specific trial. Management is supportive. Suggested NCIT terms below are listed in CLAUDE.md, but verify each before use.

  • Physical therapy: NCIT:C15302, therapeutic_modality: BEHAVIORAL.
  • Rehabilitation: NCIT:C15315.
  • Orthotics / ankle-foot orthoses: a device; bind the action and use a device qualifier per CLAUDE.md.
  • Orthopaedic surgery for foot deformity or scoliosis: NCIT:C16186, SURGERY.
  • Genetic counselling: NCIT:C15240.
  • Levodopa for parkinsonism: NCIT:C15986 pharmacotherapy plus a CHEBI levodopa therapeutic_agent (look the CHEBI ID up).
  • Response: good in the Italian proband (Saveri, "responsive to L‐DOPA treatment"), moderate in the juvenile case (Sanchez).
  • Hearing aids for sensorineural hearing loss.
  • Experimental, preclinical only:
  • Cystamine raised HSJ1a and HSJ1b levels in fibroblasts. This was shown in a heterozygous VUS line, so its relevance to recessive null HMNR5 is weak.
    • PMID:40423229: "A 48-h pretreatment with 150 μM of Cystamine increased the levels of DNAJB2 in both the control and patient's fibroblasts."
  • Gene replacement (AAV-DNAJB2) is a logical approach for a recessive loss-of-function disease but has not been reported.
  • Saveri suggests TDP-43 clearance as a possible target.
  • Pharmacogenomics: none.

13. Prevention

  • Primary: none.
  • Reproductive options: genetic counselling, carrier testing of relatives and partners in consanguineous families, prenatal or preimplantation testing once familial variants are known (25% recurrence risk for sibs).
  • Tertiary: prevent contractures and falls; monitor for scoliosis, bulbar or respiratory decline, hearing and parkinsonism.

14. Other species

No naturally occurring DNAJB2 disease is described in animals (OMIA not checked in this session).

15. Model organisms

  • No published Dnajb2-null model reproduces the disease.
  • Sarparanta 2020 mentions "studies on Dnajb2-deficient mice" only as a personal communication about antibody specificity.
  • Search MGI/IMPC for a Dnajb2 knockout allele before claiming there is none.
  • Overexpression models (relevant to mechanism, but not models of the disease):
  • HSJ1a overexpression delayed late-stage disease in SOD1-G93A ALS mice (PMID:24023695, Novoselov 2013).
  • HSJ1 overexpression reduced polyQ inclusions (PMID:28182921).
  • HSJ1 overexpression reduced SOD1-A4V inclusions in neuronal cells (Blumen).
  • HSJ1a helps clear TDP-43 (PMID:26936937).
  • For pathograph links, mark these as PERTURBS or RESCUES, not RECAPITULATES, at LOW or UNKNOWN fidelity, with a limitations note that they test gain, not loss, of HSJ1.
  • Patient-derived cells:
  • Fibroblasts (Blumen, Gess, Pradhan) and lymphoblastoid cell lines (Saveri): loss of expression.
  • HEK293 cells expressing a J-domain-deleted HSJ1b construct (Sanchez): aggregation, autophagy (LC3), lower BDNF and tau.
  • No iPSC-derived motor neurons have been reported. This gap could be recorded as a HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussion: the patient samples studied are not neurons, and why loss of a ubiquitously low-expressed chaperone is selectively toxic to motor neurons is unresolved.

Cached references for evidence

PMID Paper Content
22522442 Blumen 2012 first family, mechanism (abstract)
25274842 Gess 2014 c.229+1G>A, p.Tyr5Cys (abstract)
27449489 Sanchez 2016 deletion + parkinsonism (full text)
35286755 Saveri 2022 null variant, deafness, PD, TDP-43 (full text)
35652544 Liu 2022 myopathy (abstract)
32298515 Liu 2020 Chinese dHMN cohort (abstract)
32093037 Sarparanta 2020 review (full text)
28018906 Lupo 2016 review, founder effect (full text)
41549766 Bjelica 2026 natural history, QoL (full text)
41799927 Lerint 2026 compound het + YOPD (full text)
42806108 Ghermezcheshmeh 2026 systematic review (abstract)
40423229 Pradhan 2025 heterozygous VUS, cystamine (full text)
24023695 Novoselov 2013 SOD1 mouse overexpression
26936937 Chen 2016 TDP-43 clearance
28182921 Howarth 2017 polyQ inclusions
20395441 Claeys 2010 DNAJB2 expression in muscle
37070754 Sarparanta 2023 dominant extension; exclusion only
37470033 Fernández-Eulate 2023 non-5q SMA diagnostic yield
26752306 Lupo 2016 targeted sequencing
28031292 Ottaviani 2017 CK2 phosphorylation of UIM2

Also already in the cache: PMID:33369814, PMID:36445400 (epidemiology). Not quotable: PMID:27083531 (empty cache); PMID:38702287 (not cached). PMID:26556829 was fetched by mistake (it is an SPG11 paper); delete it rather than commit it.

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 22
Resolved 22
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 22
On topic 20
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 28
Resolved 27
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 6
Terms named correctly 6
Terms named as a different term 0

27 of 28 terms resolved to a current term; the rest could not be looked up either way.