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Hereditary neuropathy v1.500 CPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.
PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).; to: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Hereditary neuropathy v1.500 PPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP).
PMID: 38940544 Aarsand reports that variegate porphyria (VP) is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy.
PMID:11286631 Kauppinen reports a patient who following birth presented with severe bullous skin disease followed by increased fragility and keloid-like scarring. His fingers were shortened. Mental status, EEG, and CT of the head were normal, but sensory polyneuropathy was shown in especially in the upper extremities. Fine motor coordination disturbances were accompanied by minor verbal and visuospatial deficiencies. DNA from the patient showed that he is compound heterozygous for PPOX: c.35T>C, p.(Ile12Thr) and c.767C>G, p.(Pro256Arg).
PMID:10870850 Corrigall reports a 10-month-old child with fragile skin with blisters, scars, and milia most marked in sun-exposed areas. She had brachydactyly, photo-onycholysis, myopia, nystagmus, a sensory neuropathy and problems with concentration. She never had a typical acute attack. Genetic analysis showed that this patient was compound heterozygous for PPOX c.175C>T, p.(Arg59Trp) and c.1043A>G, p.(Tyr348Cys).
PMID: 8290408 Hift reports child who within days of birth developed severe blistering of the face and hands. She had brachydactyly, severe myopia and a pendular nystagmus. Neurological development was delayed with normal intelligence. She had gross sensory neuropathy of the hands and feet but no acute attacks.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP).
PMID: 38940544 Aarsand reports that variegate porphyria (VP) is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy, as reported by the previous reviewer.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
Hereditary neuropathy v1.478 SPTBN4 Arina Puzriakova Phenotypes for gene: SPTBN4 were changed from Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, 617519 to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, OMIM:617519
Hereditary neuropathy v1.476 MME Arina Puzriakova changed review comment from: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"; to: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder v3.24).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"
Hereditary neuropathy v1.476 MME Arina Puzriakova Added comment: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"
Hereditary neuropathy v1.403 TFG Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'monoallelic' only to 'both mono- and biallelic'

Monoallelic variants are associated with an adult-onset motor and sensory neuropathy (MIM# 604484), a disorder that is relevant to this panel. Biallelic variants cause a HSP (MIM# 615658) which also has been shown to involve peripheral neuropathy in complex cases. Both phenotypes have a sufficient number of unrelated cases (>3) reported to warrant a Green rating (updated publications list).
Hereditary neuropathy v1.399 SORD Sarah Leigh Classified gene: SORD as Green List (high evidence)
Hereditary neuropathy v1.399 SORD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 7 variants reported in unrelated cases. Functional studies showed undetectable SORD protein levels and increased intracellular sorbitol accumulation in patient fibroblasts compared to controls (PMID 32367058).
Hereditary neuropathy v1.399 SORD Sarah Leigh Gene: sord has been classified as Green List (High Evidence).
Hereditary neuropathy v1.398 SORD Sarah Leigh Publications for gene: SORD were set to PMID: 32367058
Hereditary neuropathy v1.397 SORD Sarah Leigh Phenotypes for gene: SORD were changed from CMT2 to Sorbitol dehydrogenase deficiency with peripheral neuropathy OMIM:618912; sorbitol dehydrogenase deficiency with peripheral neuropathy MONDO:0030055
Hereditary neuropathy v1.383 SORD Alexander Rossor gene: SORD was added
gene: SORD was added to Hereditary neuropathy. Sources: Expert list
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to PMID: 32367058
Phenotypes for gene: SORD were set to CMT2
Penetrance for gene: SORD were set to Complete
Review for gene: SORD was set to GREEN
Added comment: bialleleic variants present in more than 3 unrelated families
Sources: Expert list
Hereditary neuropathy v1.378 SPTBN4 Arina Puzriakova gene: SPTBN4 was added
gene: SPTBN4 was added to Hereditary neuropathy. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255; 32672909
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, 617519
Review for gene: SPTBN4 was set to GREEN
Added comment: At least 11 individuals from 9 unrelated families with biallelic variants in SPTBN4 reported at present. Motor neuronopathy/axonopathy was reported in 5 unrelated families. A formal evaluation by EMG/NCS was not conducted in the rest but phenotypes did include hypotonia and hyporeflexia which could be suggestive of neuropathy.
Sources: Literature
Hereditary neuropathy v1.186 OPA3 Louise Daugherty Phenotypes for gene: OPA3 were changed from to Optic atrophy 3 with cataract, 165300; 3-methylglutaconic aciduria, type III, 258501; Infantile optic atrophy, additionally, extra pyramidal disorder (chorea), ataxia, cognitive defects, axonal sensory neuropathy, autonomic neuropathy, pseudo-obstruction
Hereditary neuropathy v1.181 PEX10 Louise Daugherty Phenotypes for gene: PEX10 were changed from to Failure to thrive, facial dismorphism, agenesis of the corpus callosum, death in first year of life, axonal motor neuropathy, progressive ataxia and sensory-motor axonal neuropathy in adulthood described; Peroxisome biogenesis disorder 6A (Zellweger), 614870; Peroxisome biogenesis disorder 6B, 614871
Hereditary neuropathy v1.179 PMM2 Louise Daugherty Phenotypes for gene: PMM2 were changed from to Congenital disorder of glycosylation, type Ia, 212065; Neonatal onset, leukodystrophy, abnormal serum glycoproteins, mental retardation, hypotonia, ataxia, retinitis pigmentosa, seizures, slowly progressive neuropathy with SNCV, severe infections, hepatic insufficiency and cardiomyopathy
Hereditary neuropathy v1.162 PTEN Louise Daugherty Phenotypes for gene: PTEN were changed from multifocal demyelinating motor neuropathy, macrocephaly, autism spectrum disorder and skin hamartomas to Cowden syndrome 1, 158350; multifocal demyelinating motor neuropathy, macrocephaly, autism spectrum disorder and skin hamartomas
Hereditary neuropathy v1.161 PTEN Louise Daugherty Phenotypes for gene: PTEN were changed from to multifocal demyelinating motor neuropathy, macrocephaly, autism spectrum disorder and skin hamartomas
Hereditary neuropathy v1.121 PTEN Alexander Rossor reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: multifocal demyelinating motor neuropathy, macrocephaly, autism spectrum disorder and skin hamartomas; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy v1.121 OPA3 Alexander Rossor reviewed gene: OPA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Infantile optic atrophy, additionally, extra pyramidal disorder (chorea), ataxia, cognitive defects, axonal sensory neuropathy, autonomic neuropathy, pseudo-obstruction; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.81 MTTP Alexander Rossor edited their review of gene: MTTP: Added comment: Causes a progressive sensory neuropathy related to vitamin E deficiency as part of a complex multisystem disorder; Changed rating: GREEN; Changed publications: 2991816
Hereditary neuropathy v1.64 TRPV4 Louise Daugherty Phenotypes for gene: TRPV4 were changed from Hereditary motor and sensory neuropathy, type IIc, 606071; other disorders; other disorders; others to Hereditary motor and sensory neuropathy, type IIc, 606071
Hereditary neuropathy v1.60 TRPV4 Louise Daugherty Added phenotypes Hereditary motor and sensory neuropathy, type IIc, 606071; other disorders for gene: TRPV4
Publications for gene TRPV4 were changed from 25900305; 26392352 to 20037586
Hereditary neuropathy v1.58 TRPV4 Natalie Forrester reviewed gene: TRPV4: Rating: GREEN; Mode of pathogenicity: ; Publications: 20037586; Phenotypes: other disorders, Hereditary motor and sensory neuropathy, type IIc, 606071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes