Pedro María Rodríguez Cruz

Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ)‐related disorders are rare, nonprogressive, autosomal recessive conditions primarily characterized by cerebellar ataxia, hypotonia, intellectual disability, delayed ambulation, and, in some cases, quadrupedal locomotion. Pathogenic variants in four disease genes, VLDLR , CA8 , WRD81 , and ATP8A2, have been linked to these disorders, with cases reported across various ethnic groups and geographic regions. However, no reports of CAMRQ1 (OMIM #224050) have been previously made from Africa. In this study, we report the first African family with four affected siblings exhibiting typical CAMRQ1 clinical features with varying levels of phenotypic severity. Genetic analysis revealed a novel missense homozygous variant (c.1694C > A; p.P565Q) in the VLDLR gene in all the affected individuals, with the parents being heterozygous. Biochemical analysis, including immunofluorescence and confocal laser microscopy, western blot, and endoglycosidase H sensitivity and resistance assay, demonstrated the retention of the p.(P565Q) VLDLR protein in the endoplasmic reticulum (ER), impairing its trafficking to the plasma membrane and thus confirming its pathogenic impact. This ER retention is expected to disrupt VLDLR‐mediated signaling pathways, including reelin signaling, thereby affecting neuronal migration. Furthermore, due to its ER retention, the p.(P565Q) is expected to induce ER stress and activate the endoplasmic reticulum‐associated degradation (ERAD) pathway. Our findings expand the genetic and geographical spectrum of CAMRQ1 and provide further functional insights into its underlying pathogenesis.

SYNE1 deficiency is an autosomal recessive disorder with a broad phenotypic spectrum, most commonly presenting as adult-onset cerebellar ataxia with or without motor neuron dysfunction. We aimed to expand this spectrum by describing the clinical and genetic findings in 2 unrelated families with early-onset motor neuron disease and virtually no cerebellar signs over time. We performed detailed clinical, neurophysiologic, and genetic studies of 2 unrelated families with juvenile amyotrophic lateral sclerosis (ALS) and biallelic variants in SYNE1. The phenotypes of both families showed onset of symptoms in childhood or adolescence, with signs of upper and lower motor neuron dysfunction in multiple territories suggestive of juvenile ALS. Patients developed progressive muscle weakness, eventually leading to respiratory distress and bulbar signs. Whole-exome sequencing identified SYNE1 biallelic truncating variants in both families: a homozygous nonsense variant, c.23131C>T (p.Gln7711*), in Family 1, and a novel homozygous splice-site variant, c.17851-1G>A, in Family 2. Notably, mild or no cerebellar manifestations were observed during the follow-up. This report highlights a novel phenotype of SYNE1 deficiency characterized by early-onset motor neuron disease and virtually no cerebellar manifestations, broadening the phenotypic spectrum of this complex neurodegenerative disease. These findings support investigating SYNE1 variants in juvenile ALS and including SYNE1 in motor neuron disease gene panels.

Introduction: Distal hereditary motor neuropathies (dHMN) constitute a rare heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Their clinical and electrophysiological presentation is very variable due to the genetic heterogeneity of these latter. Among the rare autosomal recessive forms of dHMN, mutations in the SIGMAR1 gene have recently been described and are responsible for variable phenotypes. Below, we describe the clinical, electrophysiological, and genetic features of two patients with dHMN linked to a mutation in the SIGMAR1 gene. Observations: The two patients, aged 15 and 19 at consultation, exhibited distal limb weakness beginning at ages 9 and 10, with progressive worsening that initially affected the lower limbs and later involved the upper limbs. The second patient had a first-degree consanguinity. Clinical examination revealed pes cavus in the first patient and equinovarus feet (in the second). Both showed distal motor deficits in the lower limbs without sensory involvement. Neurography showed very reduced or nearly absent motor response amplitudes in both cases, with preserved sensory potentials. Needle EMG revealed a pattern of chronic denervation Our two patients benefited from a whole exome sequencing from the DNA extracted from whole blood and the same genetic variant (variant c.580C>T) was identified homozygotically in the SIGMAR1 gene (genomic position 9:34635721 based on the reference genome version GRCh37). Given the autosomal recessive mode of transmission, genetic counseling was offered to affected families, informing them of the 25% risk of transmitting the causal mutation to their offspring. Conclusion: dHMN is a rare condition, and cases caused specifically by mutations in the SIGMAR 1 gene are even more uncommon. Since only a few patients with this mutation have been described in scientific literature, it is difficult to know exactly what phenotypes are linked to it. To improve our understanding, it xould be helpful to conduct more genetic studies and identify additional cases, which would add valuable information to what is already known.

The neuromuscular junction (NMJ) is a highly specialized synapse between a motor neuron nerve terminal and its muscle fiber that are responsible for converting electrical impulses generated by the motor neuron into electrical activity in the muscle fibers. On arrival of the motor nerve action potential, calcium enters the presynaptic terminal, which leads to the release of the neurotransmitter acetylcholine (ACh). ACh crosses the synaptic gap and binds to ACh receptors (AChRs) tightly clustered on the surface of the muscle fiber; this leads to the endplate potential which initiates the muscle action potential that results in muscle contraction. This is a simplified version of the events in neuromuscular transmission that take place within milliseconds, and are dependent on a tiny but highly structured NMJ. Much of this review is devoted to describing in more detail the development, maturation, maintenance and regeneration of the NMJ, but first we describe briefly the most important molecules involved and the conditions that affect their numbers and function. Most important clinically worldwide, are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS), each of which causes specific molecular defects. In addition, we mention the neurotoxins from bacteria, snakes and many other species that interfere with neuromuscular transmission and cause potentially fatal diseases, but have also provided useful probes for investigating neuromuscular transmission. There are also changes in NMJ structure and function in motor neuron disease, spinal muscle atrophy and sarcopenia that are likely to be secondary but might provide treatment targets. The NMJ is one of the best studied and most disease-prone synapses in the nervous system and it is amenable to in vivo and ex vivo investigation and to systemic therapies that can help restore normal function.

Objective To determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs). Methods The effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations. Results In the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. In the presence of MuSK-MG sera, the AChR clusters were reduced, as expected, but NSC-87877 was able to protect or restore the clusters. Two purified MuSK-MG IgG4 preparations inhibited both MuSK phosphorylation and AChR cluster formation, and in both, clusters were restored with NSC-87877. Conclusions Stimulating the agrin-LRP4-MuSK-DOK7 AChR clustering pathway with NSC-87877, or other drugs, could represent a novel therapeutic approach for MuSK-MG and could potentially improve other NMJ disorders with reduced AChR numbers or disrupted NMJs.

MUSK encodes the muscle‐specific receptor tyrosine kinase (MuSK), a key component of the agrin‐LRP4‐MuSK‐DOK7 signaling pathway, which is essential for the formation and maintenance of highly specialized synapses between motor neurons and muscle fibers. We report a patient with severe early‐onset congenital myasthenic syndrome and two novel missense mutations in MUSK (p.C317R and p.A617V). Functional studies show that MUSK p.C317R, located at the frizzled‐like cysteine‐rich domain of MuSK, disrupts an integral part of MuSK architecture resulting in ablated MuSK phosphorylation and acetylcholine receptor (AChR) cluster formation. MUSK p.A617V, located at the kinase domain of MuSK, enhances MuSK phosphorylation resulting in anomalous AChR cluster formation. The identification and evidence for pathogenicity of MUSK mutations supported the initiation of treatment with β2‐adrenergic agonists with a dramatic improvement of muscle strength in the patient. This work suggests uncharacterized mechanisms in which control of the precise level of MuSK phosphorylation is crucial in governing synaptic structure.