DNMT1-associated sensory neuropathy and cerebellar ataxia: A novel variant and review of genotype-phenotype correlation.

AIM: Hereditary sensory neuropathy (HSN) 1E is a neurodegenerative disorder caused by pathogenic variants in DNA methyltransferase 1 (DNMT1). It is characterised by sensorineural deafness, sensory neuropathy and cognitive decline. Variants in DNMT1 are also associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy. METHODS: A 42-year-old man presented with imbalance, lancinating pain, numerous paucisymptomatic injuries, progressive deafness since his mid-20s, mild cognitive decline and apathy. Examination revealed abnormalities of eye movements, distal sensory loss to all modalities, areflexia without weakness and lower limb ataxia. MRI brain and FDG-PET scan demonstrated biparietal and cerebellar atrophy/hypometabolism. Whole exome sequencing detected a heterozygous likely pathogenic missense variant in DNMT1, c.1289G > A, p.Cys430Tyr. Cochlear implant was performed at 44 years for the bilateral high frequency sensorineural hearing loss with improvement in hearing and day-to-day function. RESULTS AND CONCLUSION: We describe a novel variant in DNMT1 and confirm that an overlapping HSN1E-cerebellar phenotype can occur. Only one prior case of cochlear implant in HSN1E has been reported to date but this case adds to that literature, suggesting that cochlear implant can be successful in such patients. We further explore the clinical and radiological signature of the cognitive syndrome associated with this disorder.

Neurophysiological and ophthalmological findings of SPG7-related spastic ataxia: a phenotype study in an Irish cohort.

BACKGROUND: Mutations in SPG7 are increasingly identified as a common cause of spastic ataxia. We describe a cohort of Irish patients with recessive SPG7-associated phenotype. METHODS: Comprehensive phenotyping was performed with documentation of clinical, neurophysiological, optical coherence tomography (OCT) and genetic data from individuals with SPG7 attending two academic neurology units in Dublin, including the National Ataxia Clinic. RESULTS: Thirty-two symptomatic individuals from 25 families were identified. Mean age at onset was 39.1 years (range 12-61), mean disease duration 17.8 years (range 5-45), mean disease severity as quantified with the scale for the assessment and rating of ataxia 9/40 (range 3-29). All individuals displayed variable ataxia and spasticity within a spastic-ataxic phenotype, and additional ocular abnormalities. Two had spasmodic dysphonia and three had colour vision deficiency. Brain imaging consistently revealed cerebellar atrophy (n = 29); neurophysiology demonstrated a length-dependent large-fibre axonal neuropathy in 2/27 studied. The commonest variant was c.1529C > T (p.Ala510Val), present in 21 families. Five novel variants were identified. No significant thinning of average retinal nerve fibre layer (RNFL) was demonstrated on OCT (p = 0.61), but temporal quadrant reduction was evident compared to controls (p < 0.05), with significant average and temporal RNFL decline over time. Disease duration, severity and visual acuity were not correlated with RNFL thickness. CONCLUSIONS: Our results highlight that recessive SPG7 mutations may account for spastic ataxia with peripheral neuropathy in only a small proportion of patients. RNFL abnormalities with predominant temporal RNFL reduction are common and OCT should be considered part of the routine assessment in spastic ataxia.

Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness.

Mutations in apoptosis-inducing factor mitochondrion-associated-1 (AIFM1) cause X-linked peripheral neuropathy (Cowchock syndrome, CMT4X); however, more recently a cerebellar presentation has been described. We describe a large Irish family with seven affected males. They presented with a variable age of onset, 18 months to 39 years of age. All developed variably present sensorineural deafness, peripheral neuropathy, cerebellar ataxia, and pyramidal involvement. In addition, three had colour vision deficiency. Scale for the assessment and rating of ataxia ranged 2 to 23/40, while Charcot-Marie-Tooth neuropathy score 2 varied between 7 and 13/36. All individuals had normal cognitive assessment. Neurophysiology demonstrated length-dependent large-fibre sensorimotor axonal neuropathy, with particular involvement of superficial radial sensory responses. Brain imaging, performed in four, revealed varying extent of cerebellar atrophy, and white matter changes in one. Optical coherence tomography was abnormal in one, who had unrelated eye pathology. Four obligate female carriers were assessed clinically, two of them neurophysiologically; all were unaffected. Whole genome sequencing demonstrated a previously reported hemizygous AIFM1 mutation. Analysis for mutations in other genes associated with colour deficiency was negative. AIFM1-associated phenotype in this family demonstrated significant variability. To our knowledge, this is the first report of AIFM1-associated colour blindness. Superficial radial nerve was particularly affected neurophysiologically, which could represent a phenotypic marker towards this specific genetic diagnosis.

Waardenburg syndrome: a rare cause of inherited neuropathy due to SOX10 mutation.

Waardenburg syndrome (WS) is a rare disorder comprising sensorineural deafness and pigmentation abnormalities. Four distinct subtypes are defined based on the presence or absence of additional symptoms. Mutations in six genes have been described in WS. SOX10 mutations are usually associated with a more severe phenotype of WS with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. Here we report a 32-year-old man with a novel heterozygous missense variant in SOX10 gene, who presented with congenital deafness, Hirschsprung disease, iris heterochromia, foot deformity, and intermediate conduction velocity length-dependent sensorimotor neuropathy. This case highlights that the presence of other non-neuropathic features in a patient with presumed hereditary neuropathy should alert the clinician to possible atypical rare causes.

Anoctamin 10-Related Autosomal Recessive Cerebellar Ataxia: Comprehensive Clinical Phenotyping of an Irish Sibship.

The autosomal recessive cerebellar ataxias are a heterogeneous group of neurodegenerative disorders. Mutations in the anoctamin 10 gene (ANO10) recently have been identified as a cause of autosomal recessive spinocerebellar ataxia type 10. Comprehensive phenotypic data are provided on 3 siblings with homozygous ANO10 mutations, including detailed ocular and cognitive assessments and bladder involvement not previously described in the literature. Data also are provided on unblinded therapy with coenzyme Q10, previously reported as a possible therapy in ANO10-related ataxia. A genetic diagnosis in this family was obtained through next-generation sequencing techniques after over 10 years of expensive sequencing of individual genes using the traditional Sanger approach. Greater commercial availability of gene panels will improve the ability to obtain a genetic diagnosis in the uncommon "non-Friedreich's" recessive ataxias. Clinical recognition of these recessive ataxic syndromes will also inevitably improve as the full phenotypic spectrum is identified.

Generating hand dysaesthesiae: the "GHD phenomenon" - straight to the diagnosis.

Two Irish women presented with difficulty in completion of hair straightening, limited by upper limb dysaesthesiae due to claudication or brachial plexus entrapment induced by sustained shoulder abduction beyond 90 degrees. The first described arm pain precipitated by elevation and sustained abduction above shoulder level, particularly while using her GHD hair-straightener. Elevated arm stress test was positive and a left cervical rib was seen on chest x ray. Neurogenic thoracic outlet syndrome (TOS) was diagnosed and the cervical rib was resected. The second described arm tingling and weakness when performing tasks involving shoulder abduction and elevation, limiting GHD use to 10 min before having to rest. Upper limb blood pressure and pulses were undetectable. Erythrocyte sedimentation rate was elevated and flow on radial Doppler disappeared on abduction and elevation of each arm. A CT pulmonary angiography demonstrated features of Takayasu's arteritis. Vascular TOS was diagnosed. Symptoms resolved with corticosteroids, followed by long-term immunosuppression and anti-coagulation.

"True" sporadic ALS associated with a novel SOD-1 mutation.

Mutations in the Cu/Zn superoxide dismutase gene (SOD-1) are reported in 20% of familial amyotrophic lateral sclerosis (ALS) cases, but no definite report of a mutation in a "truly" sporadic case of ALS has been proved. We present the first case of a novel SOD-1 mutation in a patient with genetically proven sporadic ALS. This mutation (H80A) is believed to alter zinc ligand binding, and its functional significance correlates well with the aggressive clinical course and postmortem findings observed in this patient.