RESUMO
Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous hereditary disorders characterized by a slowly progressive distal pure motor neuropathy. Electrophysiology, with normal motor and sensory conduction velocities, can suggest the diagnosis of dHMN and guide the genetic study. More than thirty genes are currently associated with HMNs, but around 60 to 70% of cases of dHMN remain uncharacterized genetically. Recent cohort studies showed that HSPB1, GARS, BICB2 and DNAJB2 are among the most frequent dHMN genes and that the prevalence of the disease was calculated as 2.14 and 2.3 per 100,000. The determination of the different genes involved in dHMNs made it possible to observe a genotypic overlap with some other neurogenetic disorders and other hereditary neuropathies such as CMT2, mainly with the HSPB1, HSPB8, BICD2 and TRPV4 genes of AD-inherited transmission and recently observed with SORD gene of AR transmission which seems relatively frequent and potentially curable. Distal hereditary motor neuropathy that predominates in the upper limbs is linked mainly to three genes: GARS, BSCL2 and REEP1, whereas dHMN with vocal cord palsy is associated with SLC5A7, DCTN1 and TRPV4 genes. Among the rare AR forms of dHMN like IGHMBP2 and DNAJB2, the SIGMAR1 gene mutations as well as VRK1 variants are associated with a motor neuropathy phenotype often associated with upper motoneuron involvement. The differential diagnosis of these latter arises with juvenile forms of amyotrophic lateral sclerosis, that could be caused also by variations of these genes, as well as hereditary spastic paraplegia. A differential diagnosis of dHMN related to Brown Vialetto Van Laere syndrome due to riboflavin transporter deficiency is important to consider because of the therapeutic possibility.
RESUMO
Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR-Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.
Assuntos
Lipodistrofia , PPAR gama , Humanos , Animais , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Adipócitos , Adipogenia/genética , Lipodistrofia/genética , Lipodistrofia/metabolismo , FosfolipasesRESUMO
The RYR1 gene encodes the ryanodine-receptor 1, a key protein in the excitation-contraction coupling that takes place in muscle fibers. This receptor is the main channel responsible for calcium release from the endoplasmic reticulum [1]. A number of clinical phenotypes are linked to various mutations in this large gene as shown in a compilation established by ORPHANET (see table). In this work we describe two distinct, somewhat misleading, phenotypes in relation to pathogenic variants in this gene.
Title: La grande variabilité phénotypique des mutations du gène RYR1. Abstract: Le gène RYR1 (Ryanodine-Receptor-1) code pour une protéine-clé dans le processus de couplage excitation-contraction de la fibre musculaire. Ce récepteur est le principal canal de libération du calcium à partir du réticulum endoplasmique [1]. Un certain nombre de phénotypes cliniques sont imputables aux mutations de ce gène de grande taille comme rappelé dans la liste établie par ORPHANET (voir Encadré). Nous décrivons, dans ce travail, deux phénotypes distincts, et trompeurs à certains égards, en rapport avec des mutations de ce gène.
Assuntos
Músculo Esquelético , Canal de Liberação de Cálcio do Receptor de Rianodina , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Músculo Esquelético/fisiologia , Contração Muscular/genética , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/metabolismo , Mutação , Cálcio/metabolismoRESUMO
Rare pathogenic variants in TOR1AIP1 (OMIM 614512), coding the inner nuclear membrane protein lamin-associated protein 1 (LAP1), have been associated with a spectrum of disorders including limb girdle muscular dystrophy with cardiac involvement and a severe multisystem phenotype. Recently, Cossins et al reported two siblings with limb girdle muscular dystrophy and impaired transmission of the neuromuscular synapse, demonstrating that defective LAP1 may lead to a congenital myasthenic syndrome. Herein, we describe the association of TOR1AIP1 deficiency with congenital myasthenic syndrome in three siblings.
Assuntos
Distrofia Muscular do Cíngulo dos Membros , Síndromes Miastênicas Congênitas , Proteínas do Citoesqueleto/genética , Humanos , Laminas/genética , Proteínas de Membrana/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Síndromes Miastênicas Congênitas/genética , FenótipoAssuntos
Miastenia Gravis/diagnóstico , Síndromes Miastênicas Congênitas/diagnóstico , Adulto , Inibidores da Colinesterase/uso terapêutico , Proteínas do Citoesqueleto , Feminino , Humanos , Proteínas de Membrana , Pessoa de Meia-Idade , Mutação , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/genética , Síndromes Miastênicas Congênitas/tratamento farmacológico , Síndromes Miastênicas Congênitas/genéticaRESUMO
In hereditary neuropathies, next-generation sequencing techniques are producing a vast number of candidate gene mutations that need to be verified or excluded by careful genotype-phenotype correlation analysis. In most cases, clinical acumen is still important but needs to be combined with data from nerve conduction studies and, in some cases, from nerve biopsy examinations. Indeed, characteristic clinical, electrophysiological, and sometimes pathological features may be suggestive of a particular subtype of Charcot-Marie-Tooth (CMT) disease. Microscopical (mainly ultrastructural) human nerve biopsy patterns may be related to CMT diseases and gene defects. Even today, it is important to recognize these characteristic lesions in the context of a chronic idiopathic neuropathy as they may help search for or reveal a sporadic form of CMT. In practice, these different types of lesions are often linked to the known function of the mutated genes. Only a few patients diagnosed or suspected as having a CMT disease need a nerve biopsy that can help find or confirm the causative gene mutation. The indication for this procedure should be based on a case-by-case discussion.
Assuntos
Biópsia/métodos , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Tecido Nervoso/patologia , Estudos de Associação Genética , HumanosRESUMO
BACKGROUND: Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. OBJECTIVE: We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. RESULTS: 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. CONCLUSION: AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing.
Assuntos
Amidinotransferases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Creatina/uso terapêutico , Deficiência Intelectual/tratamento farmacológico , Doenças Musculares/tratamento farmacológico , Distúrbios da Fala/tratamento farmacológico , Adolescente , Amidinotransferases/química , Amidinotransferases/genética , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Criança , Pré-Escolar , Creatina/deficiência , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Expressão Gênica , Genes Recessivos , Glicina/análogos & derivados , Glicina/sangue , Glicina/deficiência , Glicina/urina , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/fisiopatologia , Mutação , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Análise de Sequência de DNA , Distúrbios da Fala/diagnóstico , Distúrbios da Fala/genética , Distúrbios da Fala/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C ), we propose a simplified classification such as AR CMT1 (A, B, C ), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment.
Assuntos
Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/genética , Neuropatia Hereditária Motora e Sensorial/classificação , Neuropatia Hereditária Motora e Sensorial/genética , Doença de Charcot-Marie-Tooth/patologia , Doenças Desmielinizantes/patologia , Feminino , Testes Genéticos , Neuropatia Hereditária Motora e Sensorial/patologia , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Nervos Periféricos/metabolismo , Nervos Periféricos/patologiaAssuntos
Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Adulto , Argélia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Adulto JovemRESUMO
The prevalence of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR-CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino-varus, claw-like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR-CMT.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Doença de Charcot-Marie-Tooth/epidemiologia , Genes Recessivos , Genótipo , Humanos , FenótipoRESUMO
BACKGROUND/AIMS: The prevalence of epilepsy in Algeria is unknown. The aims of this multicenter transversal study were to determine the national prevalence and clinical characteristics of epilepsy in the Algerian population. METHODS: This two-phase study was conducted in 5 circumscriptions and included 8,046 subjects aged over 2 months who attended the randomly selected public and private primary care clinics. In the phase 1 study, a questionnaire was submitted to the sample of patients. In the phase 2 study, all potentially epileptic people were examined by neurologists and a second questionnaire was submitted, eventually assessed by appropriate investigations. RESULTS: Sixty-seven patients were identified as having active epilepsy, giving a crude prevalence ratio of 8.32 per 1,000 (95% CI, 6.34-10.3) and an age-adjusted prevalence ratio of 8.9 per 1,000. The highest age-specific ratio was found in patients aged 10-19 years (16.92 per 1,000). Generalized seizures (68.7%) were more common than partial seizures (29.8%). Perinatal injuries were the major leading putative causes (11.9%). CONCLUSION: The prevalence of epilepsy of 8.32 determined in this study is relatively high. These results provide new epidemiological data and suggest that epilepsy remains an important public health issue to consider in Algeria.
Assuntos
Epilepsia/epidemiologia , Adolescente , Adulto , Idoso , Argélia/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Proteínas de Membrana/genética , Mutação/genética , Fenótipo , Proteínas Tirosina Fosfatases não Receptoras/genética , Adolescente , Argélia , Doença de Charcot-Marie-Tooth/etnologia , Criança , Feminino , Humanos , Incidência , Masculino , Linhagem , Estudos Retrospectivos , Escoliose/epidemiologia , Escoliose/genética , Tórax/anormalidades , Paralisia das Pregas Vocais/epidemiologia , Paralisia das Pregas Vocais/genética , Adulto JovemAssuntos
Predisposição Genética para Doença/genética , Mutação/genética , Doenças Neurodegenerativas/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Criança , Pré-Escolar , Saúde da Família , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Adulto JovemRESUMO
Giant axonal neuropathy (GAN), a severe childhood disorder affecting both the peripheral nerves and the central nervous system, is due to mutations in the GAN gene encoding gigaxonin, a protein implicated in the cytoskeletal functions and dynamics. In the majority of the GAN series reported to date, patients had the classical clinical phenotype characterized by a severe axonal neuropathy with kinky hair and early onset CNS involvement including cerebellar and pyramidal signs. We present 12 patients (6 families) with GAN mutations and different clinical phenotypes. Four families were harbouring an identical homozygous nonsense mutation but with different severe clinical phenotypes, one patient had a novel missense homozygous mutation with a peculiar moderate phenotype and prominent skeletal deformations. The last family (4 patients) harbouring a homozygous missense mutation had the mildest form of the disease. In contrast with recent reported series of patients with typical GAN clinical features, the present series demonstrate obvious clinical heterogeneity.