RESUMEN
Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.
Asunto(s)
Edad de Inicio , Neuropatía Hereditaria Motora y Sensorial/genética , Adolescente , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Neuropatía Hereditaria Motora y Sensorial/patología , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Lactante , Persona de Mediana Edad , Mutación , Fenotipo , Adulto JovenRESUMEN
The hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of upper-motor-neuron degenerative diseases characterized by selective axonal loss in the corticospinal tracts and dorsal columns. Although numerous mechanisms involving defective subcellular transportation, mitochondrial malfunction, and increased oxidative stress have been proposed, the pathogenic basis underlying the neuronal loss is unknown. We have performed linkage analysis to refine the extent of the SPG5 disease locus and conducted sequence analysis of the genes located within this region. This identified sequence alterations in the cytochrome P450-7B1 (CYP7B1) associated with this pure form of HSP. In the liver, CYP7B1 offers an alternative pathway for cholesterol degradation and also provides the primary metabolic route for the modification of dehydroepiandrosterone neurosteroids in the brain. These findings provide the first direct evidence of a pivotal role of altered cholesterol metabolism in the pathogenesis of motor-neuron degenerative disease and identify a potential for therapeutic intervention in this form of HSP.
Asunto(s)
Colesterol/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Homeostasis/genética , Paraplejía Espástica Hereditaria/genética , Esteroide Hidroxilasas/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Familia 7 del Citocromo P450 , Humanos , Hígado/metabolismo , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADN , Paraplejía Espástica Hereditaria/metabolismoRESUMEN
Patients with a recessively inherited "pure" hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 alpha hydroxylase (CYP7B1). One of the expected metabolic consequences of such mutations is accumulation of oxysterol substrates due to decreased enzyme activity. In accordance with this, we demonstrate here that four patients with the SPG5 disease have 6- to 9-fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30- to 50-fold, was found in cerebrospinal fluid. The plasma levels of 25-hydroxycholesterol were increased about 100-fold. There were no measurable levels of this oxysterol in cerebrospinal fluid. The pattern of bile acids in serum was normal, suggesting a normal bile acid synthesis. The findings are discussed in relation to two transgenic mouse models with increased levels of 27-hydroxy cholesterol in the circulation but without neurological symptoms: the cyp27a1 transgenic mouse and the cyp7b1 knockout mouse. The absolute plasma levels of 27-hydroxycholesterol in the latter models are, however, only about 20% of those in the SPG5 patients. If the accumulation of 27-hydroxycholesterol is an important pathogenetic factor, a reduction of its levels may reduce or prevent the neurological symptoms. A possible strategy to achieve this is discussed.
Asunto(s)
Hidroxicolesteroles/sangre , Hidroxicolesteroles/líquido cefalorraquídeo , Paraplejía Espástica Hereditaria/sangre , Paraplejía Espástica Hereditaria/líquido cefalorraquídeo , Esteroide Hidroxilasas/genética , Adulto , Ácidos y Sales Biliares/sangre , Familia 7 del Citocromo P450 , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/sangre , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/etiología , Padres , Fosforilación , Paraplejía Espástica Hereditaria/complicaciones , Paraplejía Espástica Hereditaria/genética , Proteínas tau/líquido cefalorraquídeoRESUMEN
We describe a patient with a longstanding history of hypertrophic neuropathy of Dejerine-Sottas type, ultimately diagnosed with CMT1E disease due to a new p.Leu18Arg missense mutation in the first transmembrane domain of the PMP22 gene. The patient never walked independently and was wheelchair bound by age 18 years. Her parents and son were unaffected. Her peroneal muscular atrophy syndrome presented with scoliosis, bilateral hearing loss, pes planus, distal sensory loss and generalized areflexia. A nerve biopsy at age 26 years showed nerve hypertrophy, myelin uncompaction, defects in mesaxon formation, Schwann cells with irregular outline, axons incompletely surrounded by Schwann cell processes and very short internodes interspersed with denuded axons. Large, mostly denervated, onion bulb formations were also prominent. These findings indicate that demyelination continues undeterred in the advanced stages of the disease and is followed by remyelination attempts that recapitulate the early defects in Schwann cell/axon interaction seen in the Trembler-J mouse, which carries a mutation in the same transmembrane domain.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/patología , Proteínas de la Mielina/genética , Nervio Sural/patología , Adulto , Animales , Enfermedad de Charcot-Marie-Tooth/genética , Exones , Femenino , Humanos , Ratones , Mutación MissenseRESUMEN
A 20-year-old woman presented with mental retardation and a history of stroke related to moyamoya disease at the age of 8 years. She had cognitive impairment which became more pronounced after the stroke. This patient's parents were first cousins and six close family relatives had strokes in their 60s or 70s. The patient's 16-year-old sister had learning disability, chronic muscle pain, and an ECG suggestive of previous hypoxemic heart injury. The two sisters had similar dysmorphic facial appearance including a prominent philtrum, bulbous nose, and severe acne. They both had increased subcutaneous tissue in their faces, whereas their bodies were slim. Both sisters were found to have elevated levels of rheumatoid factor, C-reactive protein, and erythrocyte sedimentation rate on repeat measurements. Partial autoimmunity screening in one of the patients was negative. Chromosome analysis and array comparative genomic hybridization analyses were also normal. Nerve conduction findings in the younger sister were consistent with distal, predominantly motor, demyelinating neuropathy localized to the lower extremities. We propose that these two sisters suffer from a new autosomal recessive syndrome. Carrier status for this condition may predispose to later onset stroke.
Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedad de Moyamoya/genética , Adolescente , Trastorno Dismórfico Corporal/genética , Disfunción Cognitiva/genética , Hibridación Genómica Comparativa , Femenino , Genes Recesivos/genética , Humanos , Inflamación/genética , Hermanos , Accidente Cerebrovascular/genética , Enfermedades Vasculares/genética , Adulto JovenRESUMEN
OBJECTIVE: To report an association between spastic paraplegia type 2 with axonal peripheral neuropathy and apparent proteolipid protein gene (PLP1) silencing in a family. METHODS: Pulsed-field gel electrophoresis, custom array comparative genomic hybridization, and semi-quantitative multiplex polymerase chain reaction analyses were used to examine the PLP1 genomic region. RESULTS: Electrodiagnostic studies and a sural nerve biopsy showed features of a dystrophic axonal neuropathy. Molecular studies identified a small duplication downstream of PLP1. INTERPRETATION: We propose the duplication to result in PLP1 gene silencing by virtue of a position effect. Our observations suggest that genomic rearrangements that do not include PLP1 coding sequences should be considered as yet another potential mutational mechanism underlying PLP1-related dysmyelinating disorders.
Asunto(s)
Proteínas de la Membrana/genética , Mutación , Enfermedad de Pelizaeus-Merzbacher/genética , Enfermedades del Sistema Nervioso Periférico/genética , Análisis Mutacional de ADN/métodos , Electroforesis en Gel de Poliacrilamida/métodos , Humanos , Proteínas con Dominio MARVEL , Imagen por Resonancia Magnética/métodos , Masculino , Microscopía Electrónica de Transmisión/métodos , Conducción Nerviosa/fisiología , Hibridación de Ácido Nucleico/métodos , Enfermedad de Pelizaeus-Merzbacher/complicaciones , Enfermedad de Pelizaeus-Merzbacher/patología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/patología , Proteolípidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Nervio Sural/metabolismo , Nervio Sural/patología , Nervio Sural/ultraestructuraRESUMEN
The authors describe a family with autosomal dominant rippling muscle disease (RMD) and prominent early-onset toe walking. Molecular analysis revealed a novel heterozygous G > A transition at nucleotide position 136 in exon 2 of the caveolin-3 gene (CAV3). The role of Achilles tendon lengthening in more severe forms of RMD is discussed.