Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.

De novo p.Glu61Ter mutation in GCH1 in a Moroccan patient with dopa-responsive dystonia: a case report.

Dopa-responsive dystonia (DRD) is a hereditary movement disorder due to a selective nigrostriatal dopamine deficiency. It is characterized by onset in childhood or adolescence with marked diurnal fluctuation with or without Parkinsonian features, and is caused by mutations in GCH1 gene. We report in this study the clinical and genetic features of the first DRD Moroccan patient. Using a gene panel sequencing, we identified a heterozygous nonsense variant p. Glu61Ter in GCH1. A subsequent targeted segregation analysis by Sanger sequencing validated the presence of the mutation in the patient, which was found to have occurred de novo. The objective of this study is to report the first description of DRD in Morocco, and highlights the importance of new generation sequencing technology in the reduction of medical wandering and the management of hereditary diseases.

Stiff Person Syndrome With Positive Anti-glutamic Acid Decarboxylase (GAD) Autoantibodies.

Stiff person syndrome (SPS) is a progressive autoimmune disorder characterized by muscle rigidity, frequent falls, and spasms, affecting primarily women. Recent advances have linked SPS to specific antibodies, such as anti-glutamic acid decarboxylase (GAD)-65, but effective treatments remain elusive. We report the case of a 53-year-old female who developed chronic lower back pain, tingling paresthesias, and progressive rigidity in the lower limbs. Electromyographic examination revealed muscle spasms and co-contractions, along with severe rigidity and reactive spasms upon touch. Imaging studies showed a polymyomatous uterus and no hypermetabolic lesions. She was diagnosed with stiff person syndrome with positive anti-GAD65 autoantibodies. Patient was treated with methylprednisolone, oral corticosteroids, gabapentin, baclofen, alprazolam, immunoglobulins, and rituximab, leading to moderate improvement in her condition. This case report aims to highlight the association between SPS and anti-GAD65 autoantibodies, emphasizing the importance of early diagnosis and comprehensive management.

The validity of the upper limb neurodynamic test 2A in women with a clinical diagnosis of carpal tunnel syndrome: a prospective diagnostic accuracy study.

Introduction: the validity of the upper limb neurodynamic tests and especially the upper limb neurodynamic test 1 for diagnosing carpal tunnel syndrome has been the subject of several previous studies. However, the upper limb neurodynamic test 2A, which is also a test designated to assess the mechanosensitivity of the median nerve, has not been sufficiently studied, particularly for the diagnosis of carpal tunnel syndrome. Methods: we used the upper limb neurodynamic test 2A as the index test and nerve conduction studies as the reference standard. We considered the upper limb neurodynamic test 2A positive according to Nee et al. criteria. Sensitivity, specificity, positive likelihood, and negative likelihood were calculated. In addition, a receiver operating characteristics analysis was carried out. Results: ninety-four women (188 hands) suspected of carpal tunnel syndrome with a mean age of 48.87 years and SD of 12.09 participated in the study. The sensitivity of the upper limb neurodynamic test 2A was estimated at 73.4%, the specificity at 47%, the positive likelihood ratio was 1.38, the negative likelihood ratio was 0.57, and the Kappa agreement was 20.3%, and the area under the curve 60.1%. Conclusion: the upper limb neurodynamic test 2A does not seem to have value in the diagnosis of carpal tunnel syndrome when compared to nerve conduction studies. It could be alternatively used to detect an increased mechanosensitivity of the median nerve when the upper limb neurodynamic test 1 cannot be performed in case of a range of motion limitation of the shoulder abduction.

[Moderate bilateral carpal tunnel syndrome improved by median nerve neurodynamic mobilization: a case report]. / Syndrome du canal carpien bilatéral modéré amélioré par la mobilisation neurodynamique du nerf médian: à propos d'un cas.

Carpal tunnel syndrome is the most common neuropathy affecting the upper limb. Several therapeutic approaches are used to treat this syndrome, including conservative treatment, often used as the first line treatment. We here report the case of a 61-year-old female patient, presenting to the Department of Clinical Neurophysiology of the Specialty Hospital, Rabat, with moderate and bilateral carpal tunnel syndrome with sensory loss confirmed by electroneuromyography (ENMG). Manual therapy, including bilateral median nerve neurodynamic mobilization, was performed. Patient´s outcome was marked by disappearance of nocturnal numbness and follow up ENMG showed a marked improvement in nerve conduction parameters. Based on this positive result, neurodynamic mobilization of the median nerve may be considered as a possible approach for the conservative treatment of carpal tunnel syndrome.

The effectiveness of the median nerve neurodynamic mobilisation techniques in women with mild or moderate bilateral carpal tunnel syndrome: A single-blind clinical randomised trial.

Background: Carpal tunnel syndrome (CTS) is the most prevalent upper limb compression neuropathy. Surgical or nonsurgical treatment is recommended. Both mild and moderate CTS can be managed conservatively. Neurodynamic mobilisation techniques (NMTs) of the median nerve have not been widely studied, and conflicting findings exist. Methods/design: Sixty-two female patients with mild or moderate bilateral CTS were assigned one wrist to the treatment group (TG) and the other to the control group (CG). Both groups underwent carpal bone mobilisation. The TG underwent NMTs while the CG received a placebo elbow mobilisation not targeting the median nerve. The Numerical Rating Pain Scale, JAMAR Plus Digital Hand dynamometer and Functional Status Scale (FSS) were used to assess pain, grip strength and functional status. Discussion: Comparison of groups showed that NMTs at 5 weeks decreased pain intensity by 1.15 (p = 0.001) and by 2 (p ˂ 0.001) at 10 weeks. Difference in functional status was 0.45 at 5 weeks (p = 0.003) and 0.84 at 10 weeks (p = 0.003). The CG's grip strength improved by 0.59 (p = 0.05) after 5 weeks and 0.61 (p = 0.028) at 10 weeks. Both groups improved in all parameters over time. Conclusion: When combined with carpal bone mobilisation, both NMTs and placebo elbow mobilisation seem to reduce pain intensity and improve grip strength and functional status. However, NMTs had better results in pain intensity and FSS. Clinical implications: Women with mild or moderate bilateral CTS may benefit from NMTs as a conservative treatment option. Trial registration: Pan African Clinical Trials Registry, PACTR202201807752672, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=19340.

Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of hereditary motor and sensory neuropathies. Three loci for the axonal autosomal recessive subgroup (ARCMT2) have been reported in 1q21 (CMT2B1, LMNA), 8q21 (CMT4A and CMT2K, GDAP1) and 19q13 (CMT2B2). We report here a clinical, electrophysiological, pathological and genetic study in 13 Moroccan families with ARCMT2 phenotypes. Clinical and electrophysiological examinations were performed in all index cases and 64 'at-risk' relatives. Thirty-one patients were clinically affected. A peroneal nerve biopsy was obtained from three patients. Four families were linked to the 1q21 locus, all had the LMNA R298C mutation. Six families were linked to the 8q21 locus, all had the GDAP1 S194X mutation. Founder effects for both mutations were suggested by the analysis of microsatellite markers close to the genes. The three remaining families were excluded from the three known loci. The electrophysiological findings were consistent with an axonal neuropathy. The clinical data show that in CMT2B1 the disease began most often in the second decade and progressed gradually from distal to proximal muscles. Three of our patients with the longest disease durations (>24 years) had also severe impairment in the scapular muscles. Reported here for the first time, this might be a hallmark of CMT2B1. Patients with CMT4A/2K had onset most often before the age of 2 years. Most had severe clubfoot from the beginning, one of the hallmarks of CMT4A/2K. None of our patients with CMT4A/2K had vocal cord paralysis. The clinical phenotype of the three families that are not linked to the three known loci presented some particularities that were not seen in those with known genetic defects. One family was characterized by late onset of the disease (>20 years) or a mild neuropathy that was diagnosed only when the family was examined. In a second family, dorsal scoliosis was the most prominent symptom. In the third family, symptoms began in the second decade with a moderate neuropathy associated with a pronounced scoliosis. These families illustrate the extent of clinical and genetic heterogeneity in ARCMT2.

A novel GDAP1 mutation P78L responsible for CMT4A disease in three Moroccan families.

BACKGROUND: The gene encoding the ganglioside-induced-differentiation-associated protein 1 (GDAP1) has been associated with both axonal and demyelinating neuropathy. Up to date, 25 mutations in the GDAP1 gene have been reported in patients from different origins. METHODS: Three Moroccan families with early onset ARCMT1 and autosomal recessive inheritance were genotyped to test linkage to 8q21.3 and their GDAP1 gene coding exons screened for mutations. RESULTS: A novel C233T transversion at codon 78 (P78L) was detected in 6 patients from 3 unrelated families. The mutation was found to be homozygous in two families and compound heterozygous in association with the already reported S194X mutation in one family. The P78L mutation was associated with a common haplotype suggesting a Moroccan founder mutation. The patients had symptoms within the two first years of life and developed common phenotype of CMT4A with evident hoarse-voice in two cases with the longer disease duration. CONCLUSION: P78L mutation was associated with a common haplotype suggesting a common ancestor.

Clinical and genetic data of Huntington disease in Moroccan patients.

BACKGROUND: Huntington's disease (HD) occurs worldwide with prevalence varying from 0.1 to 10/100,000 depending of the ethnic origin. Since no data is available in the Maghreb population, the aim of this study is to describe clinical and genetic characteristics of Huntington patients of Moroccan origin. METHODS: Clinical and genetics data of 21 consecutive patients recruited from 2009 to 2014 from the outpatient clinic of six medical centers were analyzed. Statistical analysis was performed using descriptive statistics. RESULTS: Twenty one patients from 17 families were diagnosed positive for the IT15 gene CAG expansion. Clinical symptoms were predominantly motor (19/21). Twelve patients had psychiatric and behavioral disorders, and 11 patients had cognitive disorders essentially of memory impairment. Analysis of genetic results showed that 5 patients had reduced penetrant (RP) alleles and 16 had fully penetrant (FP) alleles. The mean CAG repeat length in patients with RP alleles was 38.4 ± 0.54, and 45.37 ± 8.30 in FP alleles. The age of onset and the size of the CAG repeat length showed significant inverse correlation (p <0.001, r = -0.754). CONCLUSION: Clinical and genetic data of Moroccan patients are similar to those of Caucasian populations previously reported in the literature.

Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene.

BACKGROUND: The first locus for demyelinating autosomal recessive Charcot-Marie-Tooth (ARCMT) disease was identified in 8q13, where mutations in GDAP1 have been found. Mutations in the same gene have been detected in families with axonal ARCMT disease. OBJECTIVE: To determine the clinical, electrophysiologic, and morphologic characteristics of a consanguineous Moroccan family with ARCMT disease associated with the S194X mutation in the GDAP1 gene. METHODS: Four patients from a consanguineous Moroccan family were examined clinically and electrophysiologically. In one patient, a morphometric and ultrastructural study of a peroneal nerve biopsy sample was performed. Mutation in the coding region of the GDAP1 gene was identified by direct sequencing. RESULTS: Neuropathy was evident early in childhood, walking was delayed in one patient, and onset of symptoms occurred before 18 months in the others. The phenotype was severe: foot deformities and disabilities involving the hands and feet developed toward the end of the first decade, followed by involvement of proximal muscles in the lower limbs, leading to loss of autonomy. Electrophysiologic findings were consistent with an axonal form of CMT disease: motor nerve conduction velocities, recordable in one patient only, were greater than 40 m/sec. Sensory nerve action potentials were either abolished or substantially reduced in amplitude. The morphologic data supported the diagnosis of axonal neuropathy, showing a marked reduction in myelinated fibers and signs of axonal regeneration, including frequent pseudo-onion bulb formations. The 4 patients in this family were homozygous for the S194X mutation in the GDAP1 gene. CONCLUSION: Electrophysiologic and pathological findings support the hypothesis of an axonal disorder in this ARCMT family with the S194X mutation in the GDAP1 gene.

Juvenile-onset permanent weakness in muscle phosphofructokinase deficiency.

We describe a 41-year-old Moroccan woman with phosphofructokinase (PFK) deficiency who presented slowly progressive muscular weakness since childhood, without rhabdomyolysis episode or hemolytic anemia. Deltoid biopsy revealed massive glycogen storage in the majority of muscle fibers and polysaccharide deposits. PFK activity in muscle was totally absent. A novel homozygous non-sense mutation was detected in PFKM gene. Our observation suggests that juvenile-onset fixed muscle weakness may be a predominant clinical feature of PFK deficiency. Vacuolar myopathy with polyglucosan deposits remains an important morphological hallmark of this rare muscle glycogenosis.

[Charcot-Marie-Tooth disease]. / La maladie de Charcot-Marie-Tooth.

Charcot-Marie-Tooth (CMT) disease, also known as peroneal muscular atrophy or hereditary motor and sensory neuropathy, is among the most frequent hereditary disorders of the nervous system. The relatively homogeneous clinical phenotype involves mainly progressive weakness and wasting of distal muscles; it starts and predominates in the peroneal muscles. Electrophysiological and pathology data distinguish two principal forms of CMT: demyelinating and axonal. More than 20 distinct genetic subtypes have been identified to date and other new loci and genes remain to be discovered, thus demonstrating wide genetic heterogeneity and a number of different pathophysiological mechanisms. The classification of these different forms is based on both the mode of inheritance--autosomal dominant, recessive or X-linked--and the neuropathy type--demyelinating or axonal or "intermediate". The principal dominant forms are CMT1A, due to a duplication or point mutation in the PMP22 gene, and CMTX, due to mutations in the connexin 32 gene. Autosomal recessive forms are more frequent in North Africa. The most common involve mutations of GDAP1 or lamin A/C and generally lead to more severe phenotypes than the dominant forms. The great genetic heterogeneity necessitates a strategy for genetic diagnosis. It is based in part on the classification of the different genetic forms and in part on the phenotypic particularities and the frequency of the responsible genes in the population under study.