Early white matter involvement in an infant carrying a novel mutation in ACOX1.

We describe the clinical findings and MRI features observed in a child who presented a two-step disease course: he was hypotonic at birth and soon afterwards developed seizures, which were partially responsive to treatment; he subsequently showed developmental delay and a progressive neurological deterioration with the onset of severe seizures at around three years of age. Head MRI at age 20 days was unremarkable, whereas at 25 months it showed bilateral hyperintensity of the deep cerebellar nuclei; five months later, the signal hyperintensity was also present in the cerebellar white matter and ventral pontine fibre tracts. Molecular analysis revealed a novel ACOX1 mutation, predicting a largely truncated protein. The white matter involvement, which followed an ascending trajectory from cerebellar and brainstem structures to the cerebral hemispheres, seemed to originate from the perinuclear white matter of the deep cerebellar nuclei.

Amyotrophic lateral sclerosis causes small fiber pathology.

BACKGROUND AND PURPOSE: Our aim was to address the correlation between small fiber loss and amyotrophic lateral sclerosis (ALS) for disease onset, phenotype, genotype, duration, severity and sensory findings. METHODS: Consecutive patients referred for suspected ALS were screened. Exclusion criteria were possible ALS and previous diagnosis or known risk factors for small fiber neuropathies. A sural nerve conduction study (NCS) was bilaterally recorded. The ALS functional rating scale revised was administered and loss of functions were calculated using the Milano-Torino staging (MITOS) system. Sensory symptoms and signs were recorded. Genetic analysis was performed by the next-generation sequencing approach. Skin biopsy was performed at the distal leg and intraepidermal nerve fiber (IENF) density was quantified in three non-consecutive sections following published guidelines. Findings were referred to age- and sex-adjusted normative values. RESULTS: Fifty-seven patients including six with facial onset sensory and motor neuronopathy (FOSMN) were enrolled. Eight (15.7%) pure ALS patients and five (83%) FOSMN patients complained of sensory disturbances with different distributions. Sural NCS was normal in all except two patients. IENF density was reduced in 75.4% of pure ALS and 50% of FOSMN patients, without correlation with any disease features. IENF density was similarly reduced in bulbar (78.5%), flail limb (87.5%), pyramidal (100%), and spinal (68.2%) onset, as well as in genetic (83.3%) and sporadic (82%) ALS. There was no correlation with genotype, disease duration and severity. CONCLUSIONS: Intraepidermal nerve fiber loss is a feature of most ALS patients. It does not correlate with onset, phenotype, course and severity of the disease, and cannot be considered a clinical or prognostic biomarker.

Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis.

BACKGROUND: Optineurin (OPTN), a causative gene of hereditary primary open-angle glaucoma, has been recently associated with amyotrophic lateral sclerosis (ALS) with mainly autosomal recessive, but also dominant, traits. To further define the contribution of OPTN gene in ALS, we performed a mutational screening in a large cohort of Italian patients. METHODS: A group of 274 ALS patients, including 161 familial (FALS) and 113 sporadic (SALS) cases, were screened for OPTN mutations by direct sequencing of its coding sequence. All patients fulfilled the El Escorial criteria for probable or definite ALS and were negative for mutations in SOD1, ANG, TARDBP and FUS/TLS genes. RESULTS: The genetic analysis revealed six novel variants in both FALS and SALS patients, all occurring in an heterozygous state. We identified three missense (c.844A→C p.T282P, c.941A→T p.Q314L, c.1670A→C p.K557T), one nonsense (c.67G→T p.G23X) and two intronic mutations (c.552+1delG, c.1401+4A→G). The intronic c.552+1delG variant determined a splicing defect as demonstrated by mRNA analysis. All mutations were absent in 280 Italian controls and over 6800 worldwide glaucoma patients and controls screened so far. The clinical phenotype of OPTN-mutated patients was heterogeneous for both age of onset and disease duration but characterised by lower-limb onset and prevalence of upper motor neuron signs. CONCLUSION: In this cohort, OPTN mutations were present both in FALS (2/161), accounting for 1.2% cases, and in SALS patients (4/113), thereby extending the spectrum of OPTN mutations associated with ALS. The study further supports the possible pathological role of optineurin protein in motor neuron disease.