Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by mutations in ORNT1 gene that encodes a mitochondrial ornithine transporter. It has variable clinical presentations with episodic hyperammonemia, liver dysfunction, and chronic neurological manifestations. In this work, we report the findings of HHH syndrome in 3 Saudi siblings. The 4-year-old proband presented with recurrent Reye-like episodes, hypotonia, and multiple stroke-like lesions on brain MRI. Biochemical and molecular analysis confirmed that she had HHH syndrome. She significantly improved on protein restriction and sodium benzoate. Her two older siblings have milder phenotypes with protein intolerance and learning problems. In comparison to their sister, their homocitrulline and orotic acid were only mildly elevated even before treatment. The three patients were homozygous for a novel mutation in ORNT1 with a Gly220Arg change. In view of the CNS lesions, which initially were felt to be suggestive of MELAS, we sequenced the entire mtDNA genome and no potential pathogenic mutations were detected. Analysis of ORNT2 did not provide explanation of the clinical and biochemical variability. This work presents a yet unreported CNS involvement pattern, notably multiple supratentorial stroke-like lesions in association with HHH syndrome. Moreover, it illustrates considerable clinical/biochemical correlation, and describes a novel mutation. We suggest including HHH syndrome in the differential diagnosis of patients found to have stroke-like lesions on brain MRI.
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PMID:Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. 1782 24

Although linked with cardiac dysfunction, the association of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and pulmonary artery hypertension (PAH) has not been previously described. PAH and right ventricular heart failure were identified by echocardiography in a 3-year-old boy with a history of hypotonia, microcephaly and developmental delay. He initially presented with a 10-day history of dyspnoea, dependent oedema and reduced oral intake. Lactic acidosis was noted on serial arterial blood sampling and cerebrospinal fluid. Muscle biopsy demonstrated cytochrome-c oxidase-positive 'ragged-red' fibres consistent with MELAS; subsequent analyses revealed the m.3243A>G point mutation most commonly associated with MELAS. The mutation was heteroplasmic, representing 92% of the total mtDNA from a lung sample. Nitric oxide and epoprostenol were administered without significant clinical or echocardiographic improvement of his PAH. A 'mitochondrial cocktail' including biotin, riboflavin, carnitine and coenzyme Q10 also was provided. Five months after presentation, he developed seizures; MRI imaging of his brain demonstrated multiple focal lesions. His clinical status worsened with increasing cardiopulmonary failure. He died two months later. Although therapy for both MELAS and PAH remains limited, recent investigations suggest a beneficial role for l-arginine in both conditions, implying a possible common pathophysiology. Mitochondrial diseases such as MELAS should be considered in cases of idiopathic PAH, particularly when associated with multisystem involvement including short stature, hearing loss, renal dysfunction, retinopathy, diabetes mellitus, migraines, seizures, ophthalmoplegia, fatigability and weakness.
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PMID:Pulmonary artery hypertension in a child with MELAS due to a point mutation of the mitochondrial tRNA((Leu)) gene (m.3243A>G). 1818 Oct 29

The mitochondrial 13513G>A (D393N) mutation in the ND5 subunit of the respiratory chain complex I was initially described in association with MELAS syndrome. Recent observations have linked this mutation to Leigh disease. We screened for the 13513G>A mutation in a cohort of 265 patients with Leigh and Leigh-like disease. The mutation was found in a total of 5 patients. An additional patient who had clinical presentation consistent with a Leigh-like phenotype but with a normal brain MRI was added to the cohort. None of an additional 88 patients meeting MELAS disease criteria, nor 56 patients with respiratory chain deficiency screened for the 13513G>A were found positive for the mutation. The most frequent clinical manifestations in our patients were hypotonia, ocular and cerebellar involvement. Low mutation heteroplasmy in the range of 20-40% was observed in all 6 patients. This observation is consistent with the previously reported low heteroplasmy of this mutation in some patients with the 13513G>A mutation and complex I deficiency. However, normal complex I activity was observed in two patients in our cohort. As most patients with Leigh-like disease and the 13513G>A mutation have been described with complex I deficiency, this report adds to the previously reported subset of patients with normal respiratory complex function. We conclude that in any patient with Leigh or Leigh-like disease, testing for the 13513G>A mutation is clinically relevant and low mutant loads in blood or muscle may be considered pathogenic, in the presence of normal respiratory chain enzyme activities.
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PMID:The mitochondrial 13513G>A mutation is associated with Leigh disease phenotypes independent of complex I deficiency in muscle. 1849 10

This review aims at summarising and discussing the current status concerning the clinical presentation, pathogenesis, diagnosis, and treatment of spinal cord affection in mitochondrial disorders (MIDs). A literature search using the database Pubmed was carried out by application of appropriate search terms and their combinations. Involvement of the spinal cord in MIDs is more frequent than anticipated. It occurs in specific and non-specific MIDs. Among the specific MIDs it has been most frequently described in LBSL, LS, MERRF, KSS, IOSCA, MIRAS, and PCH and only rarely in MELAS, CPEO, and LHON. Clinically, spinal cord involvement manifests as monoparesis, paraparesis, quadruparesis, sensory disturbances, hypotonia, spasticity, urinary or defecation dysfunction, spinal column deformities, or as transverse syndrome. Diagnosing spinal cord involvement in MIDs requires a thoroughly taken history, clinical exam, and imaging studies. Additionally, transcranial magnetic stimulation, somato-sensory-evoked potentials, and cerebro-spinal fluid can be supportive. Treatment is generally not at variance compared to the underlying MID but occasionally surgical stabilisation of the spinal column may be necessary. It is concluded that spinal cord involvement in MIDs is more frequent than anticipated but may be missed if cerebral manifestations prevail. Spinal cord involvement in MIDs may strongly determine the mobility of these patients.
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PMID:Involvement of the Spinal Cord in Mitochondrial Disorders. 2972 77