Effect of nusinersen after 3 years of treatment in 57 young children with SMA in terms of SMN2 copy number or type.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1), causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. This study aimed to report on the 36-month follow-up of children with SMA treated with nusinersen before the age of 3 years. Changes in motor function, nutritional and ventilatory support, and orthopedic outcomes were evaluated at baseline and 36 months after intrathecal administration of nusinersen and correlated with SMA type and SMN2 copy number. RESULTS: We found that 93% of the patients gained new motor skills during the 3 years-standing without help for 12 of 37 and walking with help for 11 of 37 patients harboring three SMN2 copies. No patients with two copies of SMN2 can stand alone or walk. Patients bearing three copies of SMN2 are more likely to be spared from respiratory, nutritional, and orthopedic complications than patients with two SMN2 copies. CONCLUSION: Children with SMA treated with nusinersen continue to make motor acquisitions at 3 years after initiation of treatment. Children with two SMN2 copies had worse motor, respiratory, and orthopedic outcomes after 3 years of treatment than children with three copies.

The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test.

BACKGROUND: The BTB-KELCH protein Gigaxonin plays key roles in sustaining neuron survival and cytoskeleton architecture. Indeed, recessive mutations in the Gigaxonin-encoding gene cause Giant Axonal Neuropathy (GAN), a severe neurodegenerative disorder characterized by a wide disorganization of the Intermediate Filament network. Growing evidences suggest that GAN is a continuum with the peripheral neuropathy Charcot-Marie-Tooth diseases type 2 (CMT2). Sharing similar sensory-motor alterations and aggregation of Neurofilaments, few reports have revealed that GAN and some CMT2 forms can be misdiagnosed on clinical and histopathological examination. The goal of this study is to propose a new differential diagnostic test for GAN/CMT2. Moreover, we aim at identifying the mechanisms causing the loss-of-function of Gigaxonin, which has been proposed to bind CUL3 and substrates as part of an E3 ligase complex. RESULTS: We establish that determining Gigaxonin level constitutes a very valuable diagnostic test in discriminating new GAN cases from clinically related inherited neuropathies. Indeed, in a set of seven new families presenting a neuropathy resembling GAN/CMT2, only five exhibiting a reduced Gigaxonin abundance have been subsequently genetically linked to GAN. Generating the homology modeling of Gigaxonin, we suggest that disease mutations would lead to a range of defects in Gigaxonin stability, impairing its homodimerization, BTB or KELCH domain folding, or CUL3 and substrate binding. We further demonstrate that regardless of the mutations or the severity of the disease, Gigaxonin abundance is severely reduced in all GAN patients due to both mRNA and protein instability mechanisms. CONCLUSIONS: In this study, we developed a new penetrant and specific test to diagnose GAN among a set of individuals exhibiting CMT2 of unknown etiology to suggest that the prevalence of GAN is probably under-evaluated among peripheral neuropathies. We propose to use this new test in concert with the clinical examination and prior to the systematic screening of GAN mutations that has shown strong limitations for large deletions. Combining the generation of the structural modeling of Gigaxonin to an analysis of Gigaxonin transcripts and proteins in patients, we provide the first evidences of the instability of this E3 ligase adaptor in disease.

Dynamic equinus with hindfoot valgus in children with hemiplegia.

In children with hemiplegia, it is important to distinguish between equinus with hindfoot varus (equinovarus) or valgus (equinovalgus). Premature onset of medial gastrocnemius (GM) EMG in individuals with equinus is well documented. Premature onset of Peroneus longus (PL) EMG has been described in neurologically impaired adults with equinovalgus, but not in children. Our aim was to record the onset of PL and GM activity on the hemiplegic side of children with equinovalgus deformity. Fifteen children GMFCS 1 (3.8 yrs ± 2) with hemiplegia had a goniometric assessment of passive ankle range of motion and assessment of ankle function from video and surface EMG recording during gait. The clinical and video observations were used to determine the equinovalgus, as defined by Wren, at initial contact (IC). The premature onset of muscle activity was normalised as a swing (SW) percentage prior to IC of the following stance (ST). A paired T-test compared the onset of muscle activity between PL and GM. The ankle passive dorsiflexion was 13° ± 12° (hemiplegic side) versus 18° ± 10° (non-involved side) (p<0.05). For the non-involved limb, the onset of GM activity was at 14% of the gait cycle (midstance), the onset of PL activity was at 19% (p<0.05). For the hemiplegic limb with equinovalgus, there was a premature onset activity of PL (-24%) and GM(-8%) (p<0.001). On the non involved side, the onset of PL activity occurred, as in adults, after the onset of GM activity, during ST. On the hemiplegic side, there was no triceps surae contracture and the onset of PL activity occurred prior to the onset of GM activity, during terminal SW. This study confirmed the overactivity of PL in hemiplegic children with equinovalgus.

Motor and respiratory heterogeneity in Duchenne patients: implication for clinical trials.

AIMS: Our objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD). METHODS: The French dystrophinopathy database provided clinical, histochemical and molecular data of 278 DMD patients (mean longitudinal follow-up: 14.2 years). Diagnosis was based on mutation identification in the DMD gene. Three groups were defined according to the age at ambulation loss: before 8 years (group A); between 8 and 11 years (group B); between 11 and 16 years (group C). RESULTS: Motor and respiratory declines were statistically different between the three groups, as opposed to heart involvement. When acquired, running ability was lost at the mean age of 5.41 (group A), 7.11 (group B), 9.19 (group C) years; climbing stairs ability at 6.24 (group A), 7.99 (group B), 10,42 (group C) years, and ambulation at 7.10 (group A), 9.25 (group B), 12.01 (group C) years. Pulmonary growth stopped at 10.26 (group A), 12.45 (group B), 14.58 (group C) years. Then, forced vital capacity decreased at the rate of 8.83 (group A), 7.52 (group B), 6.03 (group C) percent per year. Phenotypic variability did not rely on specific mutational spectrum. CONCLUSION: Beside the most common form of DMD (group B), we provide detailed description on two extreme clinical subgroups: a severe one (group A) characterized by early severe motor and respiratory decline and a milder subgroup (group C). Compared to group B or C, four to six times fewer patients from group A are needed to detect the same decrease in disease progression in a clinical trial.

Non-lethal neonatal neuromuscular variant of glycogenosis type IV with novel GBE1 mutations.

We report a recent case of the severe congenital variant of glycogen storage disease type IV with prolonged survival. The patient was found to be a compound heterozygote for two novel mutations, a missense mutation in exon 5 (p.H188P, c.563A>C) and a severe mutation in intron 5 (c.691+2T>C). We propose that the genotype and the quality of medical care may account for the severe but non-lethal phenotype.