Dystrophin expression in a Duchenne muscular dystrophy patient with a frame shift deletion.

The exon 45 deletion is a common dystrophin gene deletion. Although this is an out-of-frame deletion, which should not allow for protein synthesis, it has been observed in mildly affected patients. We describe a patient with an exon 45 deletion who produced protein, but still had a severe Duchenne muscular dystrophy phenotype. RT-PCR analysis and cDNA sequencing from the muscle biopsy sample revealed that the exon 45 deletion induced exon skipping of exon 44, which resulted in an in-frame deletion and the production of dystrophin. A conformational change in dystrophin induced by the deletion is proposed as being responsible for the severe phenotype in the patient. We feel that the variable clinical phenotype observed in patients with the exon 45 deletion is not due to exon splicing but may be the result of other environmental or genetic factors, or both.

Familial cerebellar ataxia with muscle coenzyme Q10 deficiency.

OBJECTIVE: To describe a clinical syndrome of cerebellar ataxia associated with muscle coenzyme Q10 (CoQ10) deficiency. BACKGROUND: Muscle CoQ10 deficiency has been reported only in a few patients with a mitochondrial encephalomyopathy characterized by 1) recurrent myoglobinuria; 2) brain involvement (seizures, ataxia, mental retardation), and 3) ragged-red fibers and lipid storage in the muscle biopsy. METHODS: Having found decreased CoQ10 levels in muscle from a patient with unclassified familial cerebellar ataxia, the authors measured CoQ10 in muscle biopsies from other patients in whom cerebellar ataxia could not be attributed to known genetic causes. RESULTS: The authors found muscle CoQ10 deficiency (26 to 35% of normal) in six patients with cerebellar ataxia, pyramidal signs, and seizures. All six patients responded to CoQ10 supplementation; strength increased, ataxia improved, and seizures became less frequent. CONCLUSIONS: Primary CoQ10 deficiency is a potentially important cause of familial ataxia and should be considered in the differential diagnosis of this condition because CoQ10 administration seems to improve the clinical picture.

Can short-term administration of dexamethasone abrogate radiation-induced acute cytokine gene response in lung and modify subsequent molecular responses?

PURPOSE: To investigate the effects of short-term administration of dexamethasone (DEX) on radiation-induced responses in the mouse lung, focusing on expression of pro-inflammatory cytokine and related genes. METHODS AND MATERIALS: At indicated times after thoracic irradiation and/or drug treatment, mRNA expression levels of cytokines (mTNF-alpha, mIL-1 alpha, mIL-1 beta, mIL-2, mIL-3, mIL-4, mIL-5, mIL-6, mIFN-gamma) and related genes in the lungs of C3H/HeN mice were measured by RNase protection assay. RESULTS: Radiation-induced pro-inflammatory cytokine mRNA expression levels in lung peak at 6 h after thoracic irradiation. DEX (5 mg/kg) suppresses both basal cytokine mRNA levels and this early response when given immediately after irradiation. However, by 24 h, in mice treated with DEX alone or DEX plus radiation, there was a strong rebound effect that lasted up to 3 days. Modification of the early radiation-induced response by DEX did not change the second wave of cytokine gene expression in the lung that occurs at 1 to 2 weeks, suggesting that early cytokine gene induction might not determine subsequent molecular events. A single dose of DEX attenuated, but did not completely suppress, increases in cytokine mRNA levels induced by lipopolysaccharide (2.5 mg/kg) treatment, but, unlike with radiation, no significant rebound effect was seen. Five days of dexamethasone treatment in the pneumonitic phase also inhibited pro-inflammatory cytokine gene expression and, again, there was a rebound effect after withdrawal of the drug. CONCLUSIONS: Our findings suggest that short-term use of dexamethasone can temporarily suppress radiation-induced pro-inflammatory cytokine gene expression, but there may be a rebound after drug withdrawal and the drug does little to change the essence and course of the pneumonitic process.

Infantile spasms in two children with Williams syndrome.

We describe two children with Williams syndrome and infantile spasms. The diagnosis of Williams syndrome was confirmed by documentation of a deletion of the elastin gene/Williams syndrome region at 7q11.23. The diagnosis of infantile spasms was confirmed through the presence of interictal hypsarrhythmia. This represents one of the first reports of infantile spasms in the Williams syndrome.

Aicardi syndrome, metastatic angiosarcoma of the leg, and scalp lipoma.

An infant girl with Aicardi syndrome, scalp lipomas, and angiosarcoma of a limb is reported. The cavernous hemangioma of the leg was benign when biopsied at age 5 months but became malignant at 11 months. Angiosarcoma caused multiple distant metastases which were evident at autopsy at age 19 months. This is the first case of Aicardi syndrome associated with lipoma and metastatic angiosarcoma.

Rapid induction of cytokine gene expression in the lung after single and fractionated doses of radiation.

PURPOSE: To investigate cytokine gene expression in the lung after single and fractionated doses of radiation, and to investigate the effect of steroids and the genetic background. MATERIALS AND METHODS: Expression of cytokine genes (mTNF-alpha, mIL-1alpha, mIL-1beta, mIL-2, mIL-3, mIL-4, mIL-5, mIL-6, mIFN-gamma) in the lungs of C3H/HeJ and C57BL/6J mice was measured by RNase protection assay at different times after various doses of radiation. The effects of dexamethasone and fractionated radiation treatment on gene expression were also studied. RESULTS: IL-1beta was the major cytokine induced in the lungs of C3H/HeJ mice within the first day after thoracic irradiation. Radiation doses as low as 1 Gy were effective. Responses to 20 Gy irradiation peaked within 4-8h and subsided by 24 h. With the exception of IL-1alpha and TNF-alpha, the other cytokines that were investigated had undetectable pre-treatment mRNA levels and were not radiation inducible. Similar responses were seen in C57BL/6J mice, although TNF-alpha was induced and there were some quantitative differences. Pre-treatment of C3H/HeJ mice with dexamethasone reduced basal and induced IL-1 levels, but complete inhibition was not achieved. Dexamethasone was also effective if given immediately after irradiation. Fractionated daily doses of radiation (4 Gy/day) helped to maintain cytokine gene expression for a longer period. CONCLUSIONS: Inflammatory genes are rapidly induced in the lung by irradiation. This response cannot be readily abolished by steroid pre-treatment. Fractionated treatment schedules help to perpetuate the response.

High mitochondrial DNA T8993G mutation (<90%) without typical features of Leigh's and NARP syndromes.

Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome and maternally inherited Leigh's syndrome have been associated with T8993G point mutations in the mitochondrial adenosine triphosphatase 6 gene. Typically, NARP syndrome is characterized by developmental delay, seizures, dementia, retinitis pigmentosa, ataxia, sensory neuropathy, and proximal weakness. Usually, there is a correlation between the percentage of mutated mitochondrial DNA and clinical severity, and when mutated mitochondrial DNA is > 90%, it is often seen with Leigh's syndrome. We now report a family with mitochondrial DNA T8993G mutation in eight living members, five with mutant mitochondrial DNA >90% and one with 20% mutant mitochondrial DNA. However, their clinical features include variable combinations of seizures, behavior problems, learning disability, mental retardation, sensorineural deafness, cerebellar ataxia, and proximal muscle weakness. No retinitis pigmentosa was found in all eight living members, including a 56-year-old grandmother. Only one dead female relative was diagnosed with Leigh's syndrome on the neuropathologic examination at age 22 years, when she died of an accident. High mitochondrial DNA T8993G mutation is not always associated with typical features of Leigh's and NARP syndromes.

Congenital muscular dystrophy with complete laminin-alpha2-deficiency, cortical dysplasia, and cerebral white-matter changes in children.

Congenital muscular dystrophy consists of Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, muscle-eye-brain disease, and occidental congenital muscular dystrophy, which is further divided into laminin-alpha2-positive and laminin-alpha2-negative subgroups. These forms of congenital muscular dystrophy are frequently associated with abnormal white-matter changes, whereas the Fukuyama form, Walker-Warburg syndrome, and muscle-eye-brain disease are also frequently found to have polymicrogyria. We now report two infants with complete laminin-alpha2-deficiency who have not only abnormal cerebral white-matter lesions, but also bioccipital polymicrogyria. There are significant similarities in the clinical and cerebral manifestations among the various types of congenital muscular dystrophy. The diagnosis of the Fukuyama form, laminin-alpha2-deficiency, Walker-Warburg syndrome, and muscle-eye-brain disease cannot always be established on radiological studies alone.

A hypotonic infant with complete deficiencies of acid maltase and debrancher enzyme.

Infantile acid maltase deficiency is an autosomal recessive disease that invariably leads to death in the first 2 years of life. Debrancher deficiency, also an autosomal recessive disease, however, carriers a slowly progressive course. We report a hypotonic infant with a typical clinical course of infantile acid maltase deficiency in whom biochemical investigation revealed complete deficiencies of both acid maltase and debrancher enzyme.

Mitochondrial DNA depletion in children.

The first girl of an unrelated couple was noted to have failure to thrive since age 3 months, generalized hypotonia and weakness, hepatomegaly, hypoglycemia, and lactic acidosis at 4 months. She was found to have severe mitochondrial DNA (mtDNA) depletion and respiratory chain complex IV deficiency in both skeletal muscle and liver but without other common mtDNA mutations. Her younger brother developed vomiting at age 3 weeks and was diagnosed as having pyloric stenosis. His skeletal muscle and liver also showed severe mtDNA depletion. He developed generalized weakness and hypotonia, hepatomegaly, and lactic acidosis at age 3 months. Both siblings died of hepatic failure and hemorrhagic complication before 6 months of age. The brother also had chemical pancreatitis, which had not been reported before in mtDNA depletion in children. Severe mtDNA depletion may present with nonspecific symptoms such as vomiting, failure to thrive, and developmental delay; multiorgan involvement such as hepatomegaly, pancreatitis, and myopathy occurs later. Mitochondrial DNA depletion should be considered in the differential diagnosis in children with developmental delay or failure to thrive of unknown etiology.

Familial adrenal insufficiency, achalasia, alacrima, peripheral neuropathy, microcephaly, normal plasma very long chain fatty acids, and normal muscle mitochondrial respiratory chain enzymes.

Adrenal insufficiency has been associated with adrenoleukodystrophy and adrenomyeloneuropathy. In these diseases, plasma very long chain fatty acids are elevated. Peripheral neuropathy is frequently seen in adults with adrenomyeloneuropathy. We encountered two first cousins with adrenal insufficiency, who also developed peripheral neuropathy, achalasia, alacrima, and microcephaly. However, plasma very long chain fatty acids, pipecolic acid, phytanic acid, and cranial computed tomographic scan were normal. Muscle mitochondrial respiratory chain enzymes were also normal. This syndrome of adrenal insufficiency, achalasia, alacrima, microcephaly, and peripheral neuropathy is different from either adrenomyeloneuropathy or adrenoleukodystrophy.

Myasthenia gravis and associated autoimmune diseases in children.

Myasthenia gravis has been associated with other autoimmune disorders. We report two children with myasthenia gravis and another autoimmune disease: an 18-month-old boy with ocular myasthenia gravis and Hashimoto's disease and a 14-year-old girl presenting with autoimmune polymyositis, then generalized myasthenia gravis 2 years later. The rare combinations of myasthenia gravis and Hashimoto's disease or polymyositis in children are discussed, and we also briefly review myasthenia gravis and other associated autoimmune diseases in children.

Mitochondrial respiratory-chain defects presenting as nonspecific features in children.

Patients with mitochondrial respiratory-chain defects frequently exhibit lactic acidosis, ragged red fibers in skeletal muscle samples, and abnormal enzyme assays for the respiratory-chain complex. However, ragged red fibers and lactic acidosis are not always seen in all patients with mitochondrial respiratory-chain defects. We have encountered six children with biochemically proven respiratory chain defects, but typical ragged red fibers were not found in all six patients, and only five patients had increased serum lactate levels. Initially, they present with nonspecific features. However, persistent or progressive clinical features or multiple organ involvement eventually led to the diagnosis of respiratory-chain defects in these patients. Mitochondrial respiratory-chain defects should be considered in the differential diagnosis when persistent, progressive features and especially multiple organ involvement occur.

Partial NADH dehydrogenase defect presenting as spastic cerebral palsy.

Mitochondrial myopathies are heterogeneous disorders. They may present at any age with a variable clinical course. We report a 6-year-old boy presenting as spastic cerebral palsy for 4 years, then athetotic movements and loss of milestones. He was eventually found to have NADH dehydrogenase deficiency.

Normal somatosensory evoked potentials in a child in persistent coma.

Somatosensory evoked potentials have been useful in predicting coma outcome in children. We present a patient who failed to recover consciousness after a near-drowning episode and has remained in a vegetative state. The initial and subsequent somatosensory evoked potentials have been normal, illustrating that normal results do not necessarily portend a favorable outcome.

Congestive heart failure and cardiac thrombus as first presentations of Friedreich ataxia.

The majority of patients with Friedreich ataxia present with gait ataxia. Congestive heart failure usually is a terminal event. We report a 9-year-old boy who developed congestive heart failure and thrombus formation in the left ventricle at age 5 years and then progressive ataxia as well as other features of Friedreich ataxia; therefore, congestive heart failure and thrombus formation may rarely be the initial findings in Friedreich ataxia.

Generalized tonic-clonic status epilepticus in a child with cat-scratch disease and encephalopathy.

Cat-scratch disease occasionally can be associated with encephalopathy and present as status epilepticus. However, the majority of these patients recover without sequelae, as shown by our patient and previous reports. Cat-scratch disease with encephalopathy should be considered in the differential diagnosis of status epilepticus in children.

Recovery of cognition from persistent vegetative state in a child with normal somatosensory evoked potentials.

The absence of bilateral early cortical SEPs in a PVS due to nontraumatic coma is usually associated with failure to recover cognition or awareness, although rarely patients with bilaterally absent cortical SEPs in posttraumatic PVS may regain cognition. On the other hand, normal cortical SEPs in nontraumatic coma may be related to favorable outcomes as shown in this patient and other reports. Our patient is unique in that he had had serial normal SEPs, was in a PVS for 7 1/2 months, and recovered cognition, but not without cost in terms of damage to intellectual capability. Further long-term clinical follow-up studies to correlate clinical outcome with serial SEP data may be indicated.

Leigh syndrome, cytochrome C oxidase deficiency and hypsarrhythmia with infantile spasms.

A rare patient with infantile spasms, hypsarrhythmia, cytochrome c oxidase deficiency and Leigh syndrome is reported. Although rare, infantile spasms and Leigh syndrome may occur simultaneously. Leigh syndrome should be included in the differential diagnosis of infantile spasms.