Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.

Many neurodegenerative disorders present with sensory loss. In the group of hereditary sensory and autonomic neuropathies loss of nociception is one of the disease hallmarks. To determine underlying factors of sensory neurodegeneration we performed whole-exome sequencing in affected individuals with the disorder. In a family with sensory neuropathy with loss of pain perception and destruction of the pedal skeleton we report a missense mutation in a highly conserved amino acid residue of atlastin GTPase 3 (ATL3), an endoplasmic reticulum-shaping GTPase. The same mutation (p.Tyr192Cys) was identified in a second family with similar clinical outcome by screening a large cohort of 115 patients with hereditary sensory and autonomic neuropathies. Both families show an autosomal dominant pattern of inheritance and the mutation segregates with complete penetrance. ATL3 is a paralogue of ATL1, a membrane curvature-generating molecule that is involved in spastic paraplegia and hereditary sensory neuropathy. ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network. Mutant ATL3 p.Tyr192Cys fails to localize to branch points, but instead disrupts the structure of the tubular endoplasmic reticulum, suggesting that the mutation exerts a dominant-negative effect. Identification of ATL3 as novel disease-associated gene exemplifies that long-term sensory neuronal maintenance critically depends on the structural organisation of the endoplasmic reticulum. It emphasizes that alterations in membrane shaping-proteins are one of the major emerging pathways in axonal degeneration and suggests that this group of molecules should be considered in neuroprotective strategies.

Genetic spectrum of hereditary neuropathies with onset in the first year of life.

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.

Tuberous sclerosis complex. Forty-years of follow-up of a patient affected.

OBJECTIVES: To report the case of a patient diagnosed with tuberous sclerosis complex (TSC), describe its clinical features, diagnosis, and to attract attention on the fact that after 40 years of follow-up, the patient has presented practically all the manifestations described in the literature. METHODS: A 42-year-old man diagnosed with.TSC presented the emergency department due to left lumbar pain and self-limited gross hematuria. On clinical examination patient was haemodynamically stable, but with decrease in haemoglobin (6.8 g/dL). Abdominal CT scan showed a 20 cm diameter heterogeneous mass in the left kidney suggesting hemorrhage of an angiomyolipoma. RESULTS: Left radical nephrectomy was performed and the pathological study of the surgical specimen confirmed the diagnosis of angiomyolipoma. Inmunohistochemical staining was positive with HMB-45. CONCLUSIONS: To recommend that patients with TSC be evaluated by a multidisciplinary group of clinicians, including urologists, neurologists and dermatologists. As patients with TSC survive into adulthood they will require more intervention by the urologist. CT scan is usually enough for the diagnosis of angiomyolipomas. Complete nephrectomy is appropriate when the whole kidney has been replaced by angiomyolipoma. The identification of molecular markers (HMB-45) facilitates histopathological diagnosis.

Tuberous sclerosis complex. Forty-years of follow-up of a patient

OBJETIVOS: Presentar un caso singular de un paciente diagnosticado de esclerosis tuberosa, describirsus manifestaciones clínicas, diagnóstico, y llamar la atención sobre el hecho que, tras 40 años de seguimientoel paciente ha presentado prácticamente todas las manifestaciones descritas en la literatura.MÉTODOS: Hombre de 42 años de edad diagnosticadode esclerosis tuberosa que acude a urgencias por dolor lumbar izquierdo y hematuria macroscópica autolimitada.A la exploración física el paciente se presentabahemodinámicamente estable, pero con disminución de la hemoglobina (6.8g/ dL). El TAC abdominal mostrabauna masa heterogénea de 20 cm. de diámetro en el riñón izquierdo que sugirió hemorragia de angiomiolipoma. RESULTADOS: Se realizó nefrectomía radical izquierda y el estudio patológico de la pieza quirúrgica confirmó el diagnóstico de angiomiolipoma. El estudio inmunohistoquímicofue positivo para HMB-45.CONCLUSIONES: Recomendamos que los pacientes con esclerosis tuberosa sean evaluados por un grupo clínico multidisciplinar, que incluyan urólogos, neurólogosy dermatólogos. Como los pacientes con esclerosistuberosa llegan a la edad adulta requerirán más intervención por los urólogos. El TAC es normalmente suficiente para diagnosticar el angiomiolipoma. La nefrectomíatotal es apropiada cuando todo el riñón está reemplazado por el angiomiolipoma. La identificación de marcadores moleculares (HMB-45) facilita el diagnósticohistopatológico

OBJECTIVES: To report the case of a patient diagnosed with tuberous sclerosis complex (TSC), describe its clinical features, diagnosis, and to attract attention on the fact that after 40 years of follow-up, the patient has presented practically all the manifestations described in the literature.METHODS: A 42 year-old man diagnosed with TSC presented the emergency department due to left lumbar pain and self-limited gross hematuria. On clinicalexamination patient was haemodynamically stable, but with decrease in haemoglobin (6.8g/ dL). Abdominal CT scan showed a 20 cm diameter heterogeneous mass in the left kidney suggesting hemorrhage of anangiomyolipoma.RESULTS: Left radical nephrectomy was performed and the pathological study of the surgical specimen confirmed the diagnosis of angiomyolipoma. Inmunohistochemical staining was positive with HMB-45.CONCLUSIONS: To recommend that patients with TSC be evaluated by a multidisciplinary group of clinicians, including urologists, neurologists and dermatologists. As patients with TSC survive into adulthood they will requiremore intervention by the urologist. CT scan is usually enough for the diagnosis of angiomyolipomas. Complete nephrectomy is appropriate when the whole kidney has been replaced by angiomyolipoma. The identification of molecular markers (HMB-45) facilitates histopathological diagnosis