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11 Sep 2025	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%).
08 Sep 2025	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.
18 Dec 2020	Hereditary neuropathy v1.381	AARS	Arina Puzriakova Phenotypes for gene: AARS were changed from Charcot-Marie-Tooth, Type 2 ; Charcot Marie Tooth disease, axonal, type 2N, 613287; Charcot-Marie-Tooth, Type 2 to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
06 Sep 2019	Hereditary neuropathy v1.333	AARS	Louise Daugherty Tag new-gene-name tag was added to gene: AARS.
06 Sep 2019	Hereditary neuropathy v1.333	AARS	Louise Daugherty commented on gene: AARS: Added new-gene-name tag, new approved HGNC gene symbol for AARS is AARS1
14 May 2019	Hereditary neuropathy v1.80	AARS	Louise Daugherty Deleted their comment
09 May 2019	Hereditary neuropathy v1.80	AARS	Louise Daugherty commented on gene: AARS: Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.
29 Apr 2019	Hereditary neuropathy v1.63	AARS	Louise Daugherty commented on gene: AARS: Review and rating submitted by Natalie Forrester (SWGLH - Bristol Genetics) on behalf of South West GLH for GMS Neurology specialist test group.
29 Apr 2019	Hereditary neuropathy v1.60	AARS	Louise Daugherty Added phenotypes Charcot Marie Tooth disease, axonal, type 2N, 613287; Charcot-Marie-Tooth, Type 2 for gene: AARS Publications for gene AARS were changed from PMID: 26032230, PMID: 26392352 to 20045102; 26032230, 26392352
29 Apr 2019	Hereditary neuropathy v1.58	AARS	Natalie Forrester reviewed gene: AARS: Rating: GREEN; Mode of pathogenicity: ; Publications: 26032230, 26392352, 20045102; Phenotypes: Charcot-Marie-Tooth, Type 2 , Charcot Marie Tooth disease, axonal, type 2N, 613287; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
29 Apr 2019	Hereditary neuropathy v1.56	AARS	Louise Daugherty Source South West GLH was added to AARS.
29 Apr 2019	Hereditary neuropathy v1.55	AARS	Louise Daugherty reviewed gene: AARS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
29 Apr 2019	Hereditary neuropathy v1.52	AARS	James Polke reviewed gene: AARS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
29 Apr 2019	Hereditary neuropathy v1.51	AARS	Louise Daugherty Source NHS GMS was added to AARS.
29 Apr 2019	Hereditary neuropathy v1.50	AARS	Louise Daugherty Source London North GLH was added to AARS. Rating Changed from Green List (high evidence) to Green List (high evidence)