Hepatomioneuropatía secundaria a depleción del ADN mitocondrial / Hepatomioneuropathy secondary to mitochondrial DNA depletion

Introducción. La depleción del ADN mitocondrial (ADNmt) consiste en la presencia de un menor número de copias del genoma mitocondrial, siendo sus expresiones fenotípicas muy heterogéneas. Caso clínico. Niña de 22 meses de edad que presenta hipotonía generalizada detectada a partir de los 7 meses de edad asociada a hepatoesplenomegalia con moderada elevación de la transaminasemia, sin datos de fracaso hepático funcional ni hipoglucemia hipocetótica; progresivamente se observó el desarrollo de debilidad muscular, fracaso respiratorio, hipertensión arterial, acidosis láctica y superposición de signos miopáticos y neuropáticos en los estudios neurofisiológicos periféricos. El estudio genético molecular para la atrofia muscular espinal fue normal. El examen con microscopía óptica de la biopsia muscular fue compatible con atrofia neurogénica, con presencia en el examen ultraestructural de gotas lipídicas, acúmulos mitocondriales subsarcolémicos y de gránulos de glucógeno. Los complejos de la cadena respiratoria mitocondrial (CRM) en homogenado muscular fueron normales. El estudio genético molecular a nivel muscular demostró la presencia de una depleción del ADNmt. Conclusiones. Esta observación probablemente represente una nueva expresión fenotípica de depleción del ADNmt que se puede denominar forma hepatomioneuropática. La normalidad de la CRM en músculo no excluye la depleción del ADNmt

Introduction. Mitochondrial DNA depletion (mtDNA) is an highly heterogeneous condition characterized by a decresed number of mtDNA copies. Case report. The patient is a 22-month-old girl with generalized hypotonia, marked weakness, respiratory failure, arterial hypertension, hyperlactacidemia, hepatosplenomegaly and mild hypertransaminasemia without hepatic failure neither hypoketotic hypoglycemia. Electromyographic findings were consistent with neuromyopathy and muscle biopsy suggested a neurogenic atrophy. Electron microscopy revealed lipid droplets, subsarcolemmal accumulation of mitochondrias and glycogen granules. Respiratory chain enzime activities were normal. Genetic study in muscle showed mtDNA depletion, and the diagnosis of spinal muscular atrophy caused by survival motoneuron gene deletion was excluded. Conclusions. This case might be a novel phenotype of mtDNA depletion which could be named hepatomioneuropatyc form. A normal result of respiratory chain enzimes in muscle doesn't excluded mtDNA depletion

[Hepatomioneuropathy secondary to mitochondrial DNA depletion]. / Hepatomioneuropatía secundaria a depleción del ADN mitocondrial.

INTRODUCTION: Mitochondrial DNA depletion (mtDNA) is an highly heterogeneous condition characterized by a decreased number of mtDNA copies. CASE REPORT: The patient is a 22-month-old girl with generalized hypotonia, marked weakness, respiratory failure, arterial hypertension, hyperlactacidemia, hepatosplenomegaly and mild hypertransaminasemia without hepatic failure neither hypoketotic hypoglycemia. Electromyographic findings were consistent with neuromyopathy and muscle biopsy suggested a neurogenic atrophy. Electron microscopy revealed lipid droplets, subsarcolemmal accumulation of mitochondrias and glycogen granules. Respiratory chain enzime activities were normal. Genetic study in muscle showed mtDNA depletion, and the diagnosis of spinal muscular atrophy caused by survival motoneuron gene deletion was excluded. CONCLUSIONS: This case might be a novel phenotype of mtDNA depletion which could be named hepatomioneuropatyc form. A normal result of respiratory chain enzimes in muscle doesn't excluded mtDNA depletion.

[Aicardi-Goutières syndrome: report of two new cases]. / Síndrome de Aicardi-Goutières: aportación de dos nuevas observaciones.

INTRODUCTION: Aicardi-Goutières syndrome is an early onset autosomal recessive progressive encephalopathy, clinically characterized by acquired microcephaly, severe psychomotor delay and involvement of pyramidal and extrapyramidal tracts. Intracranial calcifications, especially at the level of the basal ganglia, white matter abnormalities, lymphocytosis and raised interferon (IFN)-alpha in blood and cerebrospinal fluid (CSF) form part of this syndrome. CASES REPORTS: We describe two unrelated infants (a 3-month-old boy and an 11-month-old girl) who both presented with hypotonia, microcephaly, and psychomotor delay. Mild choreic and dystonic movements, as well as progressive spasticity, were also observed in the girl. Extensive investigations revealed intracranial calcifications, mild CSF lymphocytosis in the boy, and raised IFN-a in blood and CSF in both patients. COMMENTS: Aicardi-Goutières syndrome should be kept in mind when investigating microcephalic and retarded patients with cerebral calcifications initially suggestive of TORCH infection. Appropriate genetic counseling should be provided.

[Duplication of the PLP gene and the classical form of Pelizaeus-Merzbacher disease]. / Duplicación del gen PLP y forma clásica de la enfermedad de Pelizaeus-Merzbacher.

INTRODUCTION: Pelizaeus-Merzbacher disease (PMD) is a rare form of sudanophilic leukodystrophy which is transmitted by recessive inheritance linked to the X chromosome. It only affects the myelin of the central nervous system (CNS) and is caused by a proteolipid protein (PLP) deficit, which is coded for in Xq21.2-q22. Presentation follows a classical or connatal pattern and is associated with nystagmus, stridor and pyramidal/extrapyramidal manifestations within the framework of a clinical picture of psychomotor retardation and regression with variable clinical course and presentation. CASE REPORT: A 37-month-old male, with sever psychomotor retardation, nystagmus and choreoathetotic movements with a stationary developmental profile. An MRI scan of the brain showed severe supratentorial hypomyelination and peripheral electrophysiological explorations (EMG and NCS) were normal. The genetic study using PCR revealed duplication in the PLP gene. CONCLUSION: This observation corresponds to a classical form of PMD, which must be taken into account when associated with: 1) Psychomotor retardation; 2) Early nystagmus; 3) Pyramidal/extrapyramidal involvement; 4) Absence of peripheral neurophysiological involvement; 5) A neuroradiological pattern of hypomyelination of the CNS.

[Phenotypic variability of deletion 22q11.2. An analysis of 16 observations with special emphasis on the neurological manifestations]. / Variabilidad fenotípica de la deleción 22q11.2. Análisis de 16 observaciones con referencia especial a las manifestaciones neurológicas.

INTRODUCTION: The microdeletion 22q11.2 affects 1/4000 live births and constitutes the most frequent interstitial chromosomal alteration in humans. It is involved in a heterogeneous series of phenotypic expressions. AIMS: To determine the most important clinical characteristics in a series of patients with this genetic molecular disorder. PATIENTS AND METHODS: We conducted a retrospective study of 16 patients who had been diagnosed, by means of FISH or PCR, as having microdeletion 22q11.2, and the following data were evaluated in a protocolised manner: sex, age, family background, characteristics of the pregnancy, birth, neonatal and post-neonatal periods, clinical and semiological data, as well as the results from the complementary explorations carried out according to the predominant pathology. RESULTS: The age at which the diagnosis was made oscillated between newly born and 8 years, with a predominance of males over females in a ratio of 3.2/1. In all, 81% of patients presented neurological disorders. Brain malformations were seen in six, hypoplasia of the anguli oris muscle in five, congenital facial palsy in three which was associated with brain malformations in one patient, retarded neurodevelopment in six cases and neurogenic arthrogryposis in one. Other findings such as congenital heart disease (75%), skeletal disorders (37%), peculiar phenotypes (31%), nephrourological disorders (19%) and hypoacusis (19%) constitute significant manifestations of the process. Some of the most noteworthy occasional events include retarded height and weight development, hypocalcemia and cleft palate. In one case involving a child whose mother suffered from chronic alcoholism, there were both phenotypic traits of this entity and of foetal alcohol syndrome at the same time. In four of the patients the FISH technique did not detect the deletion, which was confirmed by a technique involving DNA amplification with PCR. CONCLUSIONS: The presence of central and peripheral neurological alterations, together with cardiac, skeletal, renal and auditory disorders was confirmed, as was the existence of neurodevelopmental retardation and a peculiar phenotype. Both the frequency and the kind of disorder coincided with what has been described earlier. A number of facts stand out owing to their novelty. These include the high incidence of asymmetric crying facies, the existence of data compatible with foetal alcohol syndrome in one of the patients with this clinical entity, and the association with neurogenic arthrogryposis in another, which are circumstances that suggest the possibility of a causal relation with the deletion 22q11.2. Using DNA amplification with PCR is seen to be of greater diagnostic efficacy than the FISH technique.

[Mixed hypotonia, neurological regression and atrophy of the cerebellum: manifestations that suggest infantile neuroaxonal dystrophy]. / Hipotonía mixta, regresión neurológica y atrofia cerebelosa: manifestaciones sugestivas de distrofia neuroaxonal infantil.

INTRODUCTION: Infantile neuroaxonal dystrophy (INAD), or Seitelberger disease, is a neurodegenerative disease of unknown origin which is transmitted by autosomal recessive inheritance. Clinically, it courses with psychomotor stagnation and regression that begins at the age of one or two years, associated to hypotonia with mixed clinical features (segmentary and suprasegmentary) that progresses towards spastic tetraplegia and progressive optic atrophy and dementia; this leads to death before the age of ten years. AIMS. To present the case of a 30 month old child with INAD, in whom a N acetylgalactosaminidase deficiency and mitochondrial cytopathy were ruled out. CASE REPORT: Male aged 30 months with an initial overall retardation, and later regression, of psychomotor acquisitions. In the physical exploration the patient displayed serious neurological involvement with mixed hypotonia, muscular hypotrophy with generalised weakness and mild bilateral horizontal nystagmus. Complementary explorations with neuroimaging revealed a slight increase in the subarachnoid space, with atrophy of the vermis and cerebellar hemispheres. Neurophysiological tests (EMG and ENG), which were initially normal, later showed signs of denervation in the EMG, and the ENG revealed a decreased amplitude of motor responses, with preservation of conduction speed. Histological tests showed the presence of axons with axoplasm expanded by the inclusion of typical tubulovascular structures. CONCLUSION: The clinical features of our patient met all the criteria to satisfy a diagnosis of INAD, and he displayed a classic form of the disease. INAD must be considered when the clinician is faced with: 1. A clinical picture of stagnation and later regression of psychomotor development before the age of two years; 2. Hypotonia, muscular atrophy and initial overall areflexia, with later progression towards pyramidalism; 3. Initially normal EMG findings, with later signs of denervation; 4. Cerebellar atrophy (hemispheres and vermis); 5. Visual deficit, and 6. Histopathological proof of characteristic findings.

[Multiple symmetric lipomatosis associated to polyneuropathology, atrophy of the cerebellum and mitochondrial cytopathy]. / Lipomatosis simétrica múltiple asociada a polineuropatía, atrofia de cerebelo y citopatía mitocondrial.

INTRODUCTION: Multiple symmetric lipomatosis (MSL), which is predominantly found in middle aged males, is characterised by accumulations of fat in the neck, shoulders and other parts of the trunk, and sometimes associated with different neurological manifestations, both central and peripheral. Although its aetiology is unknown, it has been described as associated with mitochondrial cytopathies. AIMS. To describe the case of a young female with MSL associated with mitochondrial encephalomyopathy. CASE REPORT: Girl aged 14 with MSL, ataxia, patellar hyperreflexia, bilateral Babinski sign, pes cavus, axonal peripheral neuropathy, involvement of the optic pathway, atrophy of the cerebellum, subsarcolemmal mitochondrial accumulations in the untrastructural examination of the vastus lateralis muscle and partial deficit of complex I in the mitochondrial respiratory chain. As regards molecular genetic aspects, the most frequent mutations of the ATPase 6 gene in lymphocytes, and mtDNA deletions and tRNALys and tRNALeu(UUR) mutations in muscles were excluded. CONCLUSIONS: Despite the fact that MSL is an entity normally found in adults, the possibility of its being diagnosed in the paediatric age must be taken into account. This case is probably the second time MSL has been observed associated with mitochondrial cytopathy in this age bracket.