[Peripheral neuropathies, from diagnosis to treatment, review of the literature and lessons from the local experience]. / Les neuropathies périphériques, du diagnostic au traitement, revue de la littérature et enseignements de l'expérience locale.

Peripheral neuropathy implies damages to neurons belonging to the peripheral nervous system which includes cranial nerves, spinal nerves' roots, spinal ganglia, nerve trunks and their divisions, and, the autonomic nervous system. Peripheral neuropathies are frequent in the general population (prevalence: 2,4%). We present a review of the recent literature and highlight diagnostic approaches for certain types of neuropathies particularly the most frequent ones or those requiring peculiar attention in first-line medicine. We also present epidemiologic data and data related to sural nerve biopsies from our centre. The determination of the location and the topography of the affected sites, integrated into the global context of the patient, is essential to provide an etiologic diagnosis. The median nerve compression within the carpal tunnel and polyneuropathies are the most frequent forms of peripheral neuropathies. More than one hundred causes of polyneuropathies are described and they are divided into acquired, genetically determined and idiopathic. We highlight a largely adopted diagnostic strategy concerning polyneuropathies and describe the Guillain-Barre syndrome, the alcohol-related polyneuropathy and the controversies about the benefit of the B vitamin therapy and its dangers. At the Hôpital Erasme, since 2008, more than 1372 patients with peripheral neuropathy were identified. Results of sural nerve biopsies performed in seventeen of them do not largely differ from those of other centres of expertise. We conclude that the diagnosis of peripheral neuropathy usually requires the expertise of a neurologist, but, first line caregivers must be able to recognize and refer patient when needed.

A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome.

Although deficiency of complex I of the mitochondrial respiratory chain is a frequent cause of encephalopathy in children, only a few mutations have been reported in each of its subunits. In the absence of families large enough for conclusive segregation analysis and of robust functional testing, it is difficult to unequivocally show the causality of the observed mutations and to delineate genotype-phenotype correlations, making additional observations necessary. We observed two consanguineous siblings with an early-onset encephalopathy, medulla, brainstem and mesencephalon lesions on brain magnetic resonance imaging and death before 8 months of age, caused by a complex I deficiency. We used a homozygosity mapping approach and identified a missense mutation in the NDUFV1 gene. The mutation, p.Arg386His, affects a highly conserved residue, contiguous to a cysteine residue known to coordinate an Fe ion. This observation adds to our understanding of complex I deficiency disease. It validates the important role of Arg386 and therefore supports the current molecular model of iron-sulfur clusters in NDUFV1.

Late-onset Pompe disease (LOPD) in Belgium: clinical characteristics and outcome measures.

BACKGROUND: Late-onset Pompe disease (LOPD) is a rare, hereditary, progressive disorder that is usually characterized by limb-girdle muscle weakness and/or respiratory insufficiency. LOPD is caused by mutations in the acid alpha-glucosidase (GAA) gene and treated with enzyme replacement therapy (ERT). METHODS: We studied the clinical, brain imaging, and genetic features of the Belgian cohort of late-onset Pompe disease patients (N = 52), and explored the sensitivity of different outcome measures, during a longitudinal period of 7 years (2010-2017), including the activity limitations ActivLim score, 6 min walking distance (6MWD), 10 m walk test (10MWT), MRC sum score, and forced vital capacity (FVC) sitting/supine. RESULTS: In Belgium, we calculated an LOPD prevalence of 3.9 per million. Mean age at onset of 52 LOPD patients was 28.9 years (SD: 15.8 y), ranging from 7 months to 68 years. Seventy-five percent (N = 39) of the patients initially presented with limb-girdle weakness, whereas in 13% (N = 7) respiratory symptoms were the only initial symptom. Non-invasive ventilation (NIV) was started in 37% (N = 19), at a mean age of 49.5 years (SD: 11.9 y), with a mean duration of 15 years (SD: 10.2 y) after symptom onset. Brain imaging revealed abnormalities in 25% (N = 8) of the patients, with the presence of small cerebral aneurysm(s) in two patients and a vertebrobasilar dolichoectasia in another two. Mean diagnostic delay was 12.9 years. All patients were compound heterozygotes with the most prevalent mutation being c.-32-13 T > G in 96%. We identified two novel mutations in GAA: c.1610_1611delA and c.186dup11. For the 6MWD, MRC sum score, FVC sitting and FVC supine, we measured a significant decrease over time (p = 0.0002, p = 0.0001, p = 0.0077, p = 0.0151), which was not revealed with the ActivLim score and 10MWT (p > 0.05). CONCLUSIONS: Awareness on LOPD should even be further increased because of the long diagnostic delay. The 6MWD, but not the ActivLim score, is a sensitive outcome measure to follow up LOPD patients.

Late-onset Pompe disease associated with polyneuropathy.

Late-onset Pompe disease is caused by a glycogen deposition involving mainly striated muscle. It may also target many other tissues such as liver, smooth muscles or spine anterior horn. Glycogen accumulation in Schwann cells and in the perineurium of peripheral nerves was shown in Pompe's disease mouse models. Moreover two late-onset Pompe disease patients were reported as having a small fiber neuropathy. To the best of our knowledge an involvement of large nerve fibers was never depicted. We describe four late-onset Pompe disease patients having a concomitant polyneuropathy of undetermined etiology. Our observations reinforce the proof-of-concept supporting a potential involvement of peripheral nerves as additional organ targeted by late-onset Pompe disease. It has clinical care consequences since peripheral neuropathy in late-onset Pompe disease could worsen patient's disability and needs particular care such as proprioceptive physiotherapy.