First Case Report of Primary Carnitine Deficiency Manifested as Intellectual Disability and Autism Spectrum Disorder.

Systemic primary carnitine deficiency (PCD) is a genetic disorder caused by decreased or absent organic cation transporter type 2 (OCTN2) carnitine transporter activity, resulting in low serum carnitine levels and decreased carnitine accumulation inside cells. In early life, PCD is usually diagnosed as a metabolic decompensation, presenting as hypoketotic hypoglycemia, Reye syndrome, or sudden infant death; in childhood, PCD presents with skeletal or cardiac myopathy. However, the clinical presentation of PCD characterized by autism spectrum disorder (ASD) with intellectual disability (ID) has seldom been reported in the literature. In this report, we describe the clinical features of a seven-year-old girl diagnosed with PCD who presented atypical features of the disease, including a developmental delay involving language skills, concentration, and attention span, as well as autistic features and brain alterations apparent in magnetic resonance imaging. We aim to highlight the difficulties related to the diagnostic and therapeutic approaches used to diagnose such patients. The case reported here presented typical signs of PCD, including frequent episodes of hypoglycemia, generalized muscle weakness, decreased muscle mass, and physical growth deficits. A molecular genetic study confirmed the definitive diagnosis of the disease (c.1345T>G (p.Y449D)) in gene SLC22A5, located in exon 8. PCD can be accompanied by less common clinical signs, which may delay its diagnosis because the resulting global clinical picture can closely resemble other metabolic disorders. In this case, the patient was prescribed a carnitine-enriched diet, as well as oral carnitine at a dose of 100 mg/kg/day. PCD has a better prognosis if it is diagnosed and treated early; however, a high level of clinical suspicion is required for its timely and accurate diagnosis.

Skeletal alterations, developmental delay and new mutations in juvenile-onset Pompe disease.

Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase. In addition to the severe infantile form with cardiac involvement, late-onset variants can affect older children, adolescents (aged >1 year old) or adults. Patients with juvenile (a subgroup of late-onset type) Pompe disease typically do not have cardiac alterations e.g. hypertrophic cardiomyopathy, and the diagnosis is often difficult because it can clinically resemble myriad other neuromuscular disorders. A high level of clinical suspicion is necessary for a timely and accurate diagnosis. We describe 3 interesting cases of patients with juvenile-onset Pompe disease who presented some uncommon clinical features e.g. skeletal alterations and developmental delay, and describe a new genetic variant. Juvenile-onset Pompe disease may be accompanied by uncommon clinical signs that could delay the diagnosis of Pompe disease due to the global pictures resembling other metabolic disorders.

Autism and intellectual disability associated with mitochondrial disease and hyperlactacidemia.

Autism spectrum disorder (ASD) with intellectual disability (ID) is a life-long debilitating condition, which is characterized by cognitive function impairment and other neurological signs. Children with ASD-ID typically attain motor skills with a significant delay. A sub-group of ASD-IDs has been linked to hyperlactacidemia and alterations in mitochondrial respiratory chain activity. The objective of this report is to describe the clinical features of patients with these comorbidities in order to shed light on difficult diagnostic and therapeutic approaches in such patients. We reported the different clinical features of children with ID associated with hyperlactacidemia and deficiencies in mitochondrial respiratory chain complex II-IV activity whose clinical presentations are commonly associated with the classic spectrum of mitochondrial diseases. We concluded that patients with ASD and ID presenting with persistent hyperlactacidemia should be evaluated for mitochondrial disorders. Administration of carnitine, coenzyme Q10, and folic acid is partially beneficial, although more studies are needed to assess the efficacy of this vitamin/cofactor treatment combination.

Autism spectrum disorders associated to a deficiency of the enzymes of the mitochondrial respiratory chain.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by a combination of reciprocal social deficits, communication impairment, and rigid ritualistic interest and stereotypies. The etiology is generally multifactorial, including genetic, immunological and/or environmental factors. A group of ASD has been linked to mitochondrial dysfunction with subsequent deficiency in energy production. Patients with ASD and mitochondrial disease often show signs and symptoms uncommon to idiopathic ASD such as cardiac, pancreatic or liver dysfunction, cardiac, growth retardation, fatigability, but in some cases semiology is different. We show two clinical cases of ASD associated to a deficiency of the mitochondrial respiratory chain (complex I+III and IV) with different clinical presentations. In one case, signs and symptoms of mitochondrial disorder were mild and the second diagnosis was attained many years after that of ASD. These findings support the recent growing body of evidence that ASD can be associated with mitochondrial disorder. Children with ASD and abnormal neurologic or systemic findings should be evaluated for mitochondrial disorder.

Autism associated to a deficiency of complexes III and IV of the mitochondrial respiratory chain

Autism is the prototype of generalized developmental disorders or what today are called autism spectrum disorders. In most cases it is impossible to detect a specific etiology. It is estimated that a causative diagnosis may be shown in approximately 10-37 percent of the cases, including, congenital rubella, tuberous sclerosis, chromosome abnormalities such as fragile X syndrome and 22q13.3 deletion syndrome, Angelman, Williams, Smith-Magenis, Sotos, Cornelia de Lange, Mõbius, Joubert and Goldenhar syndromes, Ito’s hypomelanosis, as well as certain cerebral malformations and several inherited metabolic disorders. The case of a 3-year old girl is described, who was considered as autistic according to the criteria established by the DSM-IV manual for psychiatric disorders. She showed a delay in psychomotor development since she was 18 months old; she pronounces very few words (10), points to some objects, does not look up and it is hard to establish eye contact with her. She has paradoxical deafness and therefore, does not respond when called or when she is given orders, she is beginning to walk. She has not convulsions. Laboratory tests showed an anion gap of 31.6 mEq/L, lactate: 2.55: mmol/L, pyruvate: 0.06 mmol/L, and elevated lactate to/pyruvate ratio: 42.5. Under optical microscopy a muscular biopsy showed a reduction of the diameter of muscular fibers. The study of energy metabolism showed a partial deficiency of complexes III and IV of the respiratory chain, which allowed us to conclude that this was a mitochondrial dysfunction with an autistic clinical spectrum.

El autismo es el prototipo de los trastornos generalizados del desarrollo o de lo que hoy se denominan trastornos del espectro autista. En la mayoría de los casos no es posible detectar una etiología específica. Se estima que aproximadamente entre el 10 y el 37 por ciento de los casos se puede demostrar una causa específica,como la rubéola congénita, la esclerosis tuberosa, anomalías cromosómicas como el sindrome del cromasoma X frágil y la microdelección 22q13.3, los sindromes de Angelman, Williams, Smith-Magenis, Sotos, Cornelia de Lange, Mõebius, Joubert y Goldenhar, la hipomelanosis de Ito, así como algunas malformaciones cerebrales y varios trastornos metabólicos. Se describe un preescolar de 3 años de edad, de sexo femenino,catalogada como autista de acuerdo a los criterios establecidos por el manual DSM-IV para trastornos psiquiátricos. Presentaba un retraso en la adquisición de su desarrollo psicomotor desde los 18 meses, pronunciaba pocas palabras (10), señalaba algunos objetos, no utilizaba la mirada y era dificil establecer contacto ocular con ella, mostraba sordera paradójica, por lo que no respondia cuando se le llamaba ni cuando se le daban órdenes. Empezaba a caminar y no había presentado convulsiones. Los exámenes de laboratorio mostraban anión gap: 31,6 mEq/L, lactato: 2,55 mmol/L, piruvato: 0,06 mmol/L y una relación lactato/piruvato elevada de: 42,50 mmol/L. La biopsia muscular practicada reportó en la microscopía óptica disminución del diámetro de las fibras musculares y el estudio del metabolismo energético demostró una deficiencia parcial en los complejos III y IV de la cadena respiratoria, el cual nos permitió concluir que se trataba de una disfunción mitocondrial con espectro autista.

Autism associated to a deficiency of complexes III and IV of the mitochondrial respiratory chain.

Autism is the prototype of generalized developmental disorders or what today are called autism spectrum disorders. In most cases it is impossible to detect a specific etiology. It is estimated that a causative diagnosis may be shown in approximately 10-37% of the cases, including, congenital rubella, tuberous sclerosis, chromosome abnormalities such as fragile X syndrome and 22q13.3 deletion syndrome, Angelman, Williams, Smith-Magenis, Sotos, Cornelia de Lange, Möbius, Joubert and Goldenhar syndromes, Ito's hypomelanosis, as well as certain cerebral malformations and several inherited metabolic disorders. The case of a 3-year old girl is described, who was considered as autistic according to the criteria established by the DSM-IV manual for psychiatric disorders. She showed a delay in psychomotor development since she was 18 months old; she pronounces very few words (10), points to some objects, does not look up and it is hard to establish eye contact with her. She has paradoxical deafness and therefore, does not respond when called or when she is given orders, she is beginning to walk. She has not convulsions. Laboratory tests showed an anion gap of 31.6 mEq/L, lactate: 2.55: mmol/L, pyruvate: 0.06 mmol/L, and elevated lactate to/pyruvate ratio: 42.5. Under optical microscopy a muscular biopsy showed a reduction of the diameter of muscular fibers. The study of energy metabolism showed a partial deficiency of complexes III and IV of the respiratory chain, which allowed us to conclude that this was a mitochondrial dysfunction with an autistic clinical spectrum.

[Cryptococcus neoformans meningoencephalitis in immunocompetent schoolchildren]. / Meningoencefalitis por Criptococcus neoformans en escolares inmunocompetentes.

Cryptococcus neoformans meningoencephalitis is the most common fungal central nervous system infection, in people affected by the human immunodeficiency virus. It is rare in inmunocompetent children and it is often fatal. It predominates in males at a ratio of 3 to 1. We describe the cases of two school children, one male and one female, with history of contact with pigeons (Columba livea), whose clinical symptoms were fever, headache, photophobia, diplopia, ataxia and meningeal signs, with unilateral involvement of cranial nerve VI. The diagnosis was established by the isolation of Cryptococcus neoformans in culture, staining with India ink and evidence of latex antigen agglutination in the cerebrospinal fluid. The determination of antibodies to human immunodeficiency virus and quantification of CD4, CD8 and T lymphocyte cells, were normal. In the first case, a chest X-ray showed a round mass, circumscribed in the bottom half of the left lung. A brain MRI revealed an image compatible with a nodular cryptococcoma in the parietal region. A pattern of intracranial hypertension was established, with papilledema and bilateral amaurosis, that evolved unsatisfactorily, with the subsequent death of the patient. Both were treated with amphotericin B (1 mg/Kg/day) or fluconazole (6 mg/Kg/day). The second case had a favorable evolution. The Crypotococcus neoformans is not a common fungus in inmunocompetent children. Early detection of the disease and appropriate treatment is essential to achieve a better prognosis ot the disease.

Meningoencefalitis por Criptococcus neoformans en escolares inmunocompetentes / Cryptococcus neoformans meningoencephalitis in inmunocompetent children

La meningoencefalitis por Cryptococcus neoformans, es la infección fúngica mas frecuente del sistema nervioso central, en personas afectadas por el virus de inmunodeficiencia humana (VIH). Es rara en niños inmunocompetentes y a menudo es fatal; predomina en el sexo masculino en una proporción de 3 a 1. Se describen los casos de dos escolares, uno masculino y otro femenino con antecedentes de contacto con palomas (Columba livia), cuyas manifestaciones clínicas fueron fiebre, cefalea, fotofobia, diplopía, ataxia y signos meníngeos con afectación unilateral del VI nervio craneal. El diagnóstico se estableció con el aislamiento del criptococo en cultivo, la tinción con tinta china y las pruebas de aglutinación en látex en el líquido cefalorraquídeo. La determinación de anticuerpos para virus de la inmunodeficiencia humana (VIH) y la cuantificación de linfocitos T CD4 y CD8 fueron normales. En el primer caso, la radiografía de tórax mostró una masa redondeada circunscrita en la mitad inferior del pulmón izquierdo y la resonancia magnética cerebral (RNM) reveló una imagen nodular compatible con un criptococoma en la región parietal derecha; se estableció un cuadro de hipertensión endocraneana, con edema de papila y amaurosis bilateral con evolución no satisfactoria y posterior fallecimiento. El segundo caso tuvo una evolución favorable. Ambos recibieron tratamiento con anfotericina B (1 mg/kg/día) y fluconazol (6 mg/kg/día). El Cryptococcus neoformans no es un hongo usual en niños inmunocompetentes. La detección precoz de la enfermedad y el tratamiento adecuado es fundamental para lograr un mejor pronóstico de la enfermedad.

Cryptococcus neoformans meningoencephalitis is the most common fungal central nervous system infection, in people affected by the human immunodeficiency virus. It is rare in inmunocompetent children and it is often fatal. It predominates in males at a ratio of 3 to 1. We describe the cases of two school children, one male and one female, with history of contact with pigeons (Columba livea), whose clinical symptoms were fever, headache, photophobia, diplopia, ataxia and meningeal signs, with unilateral involvement of cranial nerve VI. The diagnosis was established by the isolation of Cryptococcus neoformans in culture, staining with India ink and evidence of latex antigen agglutination in the cerebrospinal fluid. The determination of antibodies to human immunodeficiency virus and quantification of CD4, CD8 and T lymphocyte cells, were normal. In the first case, a chest X-ray showed a round mass, circumscribed in the bottom half of the left lung. A brain MRI revealed an image compatible with a nodular cryptococcoma in the parietal region. A pattern of intracranial hypertension was established, with papilledema and bilateral amaurosis, that evolved unsatisfactorily, with the subsequent death of the patient. Both were treated with amphotericin B (1 mg/Kg/day) or fluconazole (6 mg/Kg/day). The second case had a favorable evolution. The Crypotococcus neoformans is not a common fungus in inmunocompetent children. Early detection of the disease and appropriate treatment is essential to achieve a better prognosis ot the disease.

[Primary hiperoxaluria: a new mutation in gen AGXT (R197Q) cause of neonatal convulsions]. / Hiperoxaluria primaria: una nueva mutación en el gen AGXT (r197q) causante de convulsiones neonatales.

Primary hyperoxaluria is a congenital innate error of the metabolism of the amino acids, that is transmitted like an autosomal recessive character. Two types of hyperoxaluria exist: the primary type I, that corresponds to the peroxisomal enzymatic deficit of the alanine glyoxylate aminotransferase in the liver (AGT) and type II, due to the deficit of the glyoxylate reductase/hydroxypyruvate reductase deficiency (GRHPR). The primary type I (AGT) is the most frequenty. We report the case of a female infant of one month of age, that on her first day post birth, presented myoclonic convulsions and tonic spasms, both during wakefullness and sleep periods, that became more frequent and did not respond to the use of anticonvulsants. The ictal Electroencephalogram presented an intermittent activity of spikes and spike-waves of high voltage in the right hemisphere. Eight minutes after the intravenous administration of 150 mg of pyridoxine, it was observed a diminution of the epileptic activity, as well as the clinical manifestations. The determination of organic acids in urine revealed an increase in the concentration levels of oxalic acid (3064 mmol/mol of creatinine). The molecular genetic study of the AGXT gene, showed the existence of a R197Q mutation in exón 5 of the patient and her father. She received treatment with pyridoxine at a dose of 50 mg/day. When she reached the age of three months both a normal electroencephalogram and biochemistry were obtained. Although it is a rare cause of neonatal convulsions, hyperoxaluria, due to new mutations is an underdiagnosed disease by neonatologists and paediatricias.

[Infantile encephalopathy associated with the MELAS A3243G mutation. Case report]. / Encefalopatía infantil asociada con la mutación A3243G MELAS.

Mitochondrial encephalopathies are a group of diseases that have as their pathogenic basis an alteration of the mitochondrial DNA (mtDNA). The MELAS phenotype (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) has been related to mutation A3243G in approximately 80% of the cases reported. MERRF (epilepsy myoclonus with ragged red fibers) has been related to mutation A8344G and A8566G of tRNA Lys. We report the case of a 7 months-old female with early clinical signs of encephalopathy associated to the A3243G mutation. Laboratory tests showed lactic acidosis and the EEG pattern was compatible with an encephalopathic process. The infant was treated with ACTH during one month, with clinical and electroencephalographic improvements. Currently, she is receiving treatment with B-vitamins, L-Carnitine and urinary alkalizing agents. It is concluded that an analysis of mtDNA must be made in infants who present convulsions, delay in their psychomotor development, lactic acidosis and an EEG pattern compatible with an encephalopathy, to rule out a mitochondrial disease.

Encefalopatía infantil asociada con la mutación A3243G MELAS / Infantile encephalopathy associated with the MELAS A3243G mutation: case report

Las Encefalopatías mitocondriales son un grupo de enfermedades que tienen base una alteración del ADN mt. (ADN mitocondrial). El fenotipo MELAS (Encefalopatía mitocondrial, con acidosis láctica y accidentes cerebro vasculares) se ha relacionado con la mutación A3243G en aproximadamente el 80 por ciento de los casos reportados. El fenotipo MERRF (epilepsia mioclónica con fibras rojas rasgadas) ha sido relacionado con las mutaciones A8344G y A8566G del tARN Lys. Se describe un lactante femenino de 7 meses de edad, con un cuadro de inicio temprano, que se acompañaba de una encefalopatía asociada a la mutación A3243G. En los exámenes de laboratorio destacaba una acidosis láctica y el estudio EEG mostraba signos compatibles con proceso encefalopático. Se administró ACTH durante un mes con mejoría clínica y encefalográfica. Actualmente recibe tratamiento a base de Vitaminas del complejo B, L-carnitina y alcalinizantes urinarios. Se concluye que en los lactantes que presentan convulsiones, retraso en su desarrollo psicomotor, acidosis láctica y el estudio encefalográfico compatible con una encefalopatía, debería realizarse análisis del ADN mt, para descartar una enfermedad mitocondrial.