Hypotonia

Central core disease (CCD) is an autosomal dominant, non-progressive myopathy characterized by hypotonia and proximal muscle weakness in infancy. CCD is named after detection of characteristic central cores that lack both mitochondria and oxidative enzyme... 

Clinical features include neonatal hypotonia, a tendency toward congenital hip dislocation and diffuse muscle weakness. Later on children are frequently of short stature and low body weight and often have long thin faces and high-arched palates. Respiratory difficulties, where present, occur early on and tend to improve with time. In others a virtually static clinical picture is seen. 

Patients with complex I deficiency may also present with severe congenital lactic acidosis, hypotonia, weakness, cardiomyopathy, and cardiorespiratory failure caus-... 

This complex contains 11 polypeptide subunits of which only one is encoded by mtDNA. Defects of complex III are relatively uncommon and clinical presentations vary. Fatal infantile encephalomyopathies have been described in which severe neonatal lactic acidosis and hypotonia are present along with generalized amino aciduria, a Fanconi syndrome of renal insufficiency and eventual coma and death. Muscle biopsy findings may be uninformative since abnormal mitochondrial distribution is not seen, i.e., there are no ragged-red fibers. Other patients present with pure myopathy in later life and the existence of tissue-specific subunits in complex III has been suggested since one of these patients was shown to have normal complex 111 activity in lymphocytes and fibroblasts. 

Leigh s syndrome (subacute necrotizing encephalomyelopathy) is characterized by a variable combination of clinical abnormalities including cerebellar ataxia, developmental delay, mental regression, deafness, optic atrophy, hypotonia, and... 

Another condition due to mutations in the RYRl gene is central core disease. This is a rare myopathy presenting in infancy with hypotonia and proximal muscle weakness. Electron microscopy reveals an absence of mitochondria in the center of many type I (see below) muscle fibers. Damage to mitochondria induced by high intracellular levels of Ca secondary to abnormal functioning of RYRl appears to be responsible for the morphologic findings. 

Hereditary triose phosphate isomerase (TPI) deficiency is an autosomal recessive disorder that has the most severe clinical manifestations of the erythroenzy-mopathies, including hemolytic anemia, neurological dysfunction, sudden cardiac death, and increased susceptibility to infection. Since the first description by Schneider et al. (S10), more than 25 unrelated families have been reported (Fll). Cases of decreased TPI activities associated with cat cry syndrome and pancytopenia were reported, whereas the correlation between TPI deficiency and these disorders was not clear. Although the degree of anemia is variable, most patients require blood transfusions. Neurological involvement, such as paraparesis, weakness, and hypotonia, is progressive in most cases. No specific therapy is available for the neuropathic manifestations of the disease, and most severely affected children fail to survive beyond the age of 5 years. 

Disorders of the human cerebellum result in three types of abnormalities. The first is hypotonia or reduced muscle tone. Another includes abnormalities in the execution of voluntary movements or ataxia (defective muscular coordination). The third type of muscular malfunction is intention tremors. These tremors differ from the resting tremors of Parkinson s disease in that they occur during a movement and are most pronounced at the end of the movement when the patient attempts to terminate it. 

Most warn of the increased risk of deformities of limb development and defects like cleft palate. A few drugs carry the risk of distinct organ defects. For example, chlorambucil may cause agenesis of the fetal kidneys Penicillamine seems to affect fetal connective tissue, causing relaxation of the skin, hypotonia, and hyper flexion of the hips and shoulders... 

Disorders of GABA Vitamin B6-dependent seizures Often an absence of succinic semialdehyde dehydrogenase Hypotonia, ataxia, mental retardation in older child. Increased urine 4-OH-butyric acid. Pyridoxine (B6-dependent disorder) Inhibitors of GABA transaminase... 

Profound acidosis with ketonuria, lactic acidosis, tachypnea, lethargy, hypotonia, seizures, unusual urinary odors. Usually severe neonatal onset... 

Other causes of PKU secondary to defective tetrahydrobiopterin synthesis include GTP cyclohydrolase deficiency and 6-pyravoyltetrahydrobiopterin synthase deficiency. Patients with either defect have psychomotor retardation, truncal hypotonia with limb hypertonia, seizures and a tendency to hyperthermia. The intravenous administration of BH4 may lower blood phenylalanine levels but this cofactor may not readily cross the blood-brain barrier. Treatment with synthetic pterin analogs or supplementation with tryptophan and carbidopa may prove more efficacious, particularly if treatment is started early in life. 

Intrauterine seizures may occur. The electroencephalogram often displays a hypsarrhythmia or a burst-suppression pattern. Patients display myoclonic jerks, hiccuping and a profound hypotonia. The few patients who survive past the first week usually sustain profound mental retardation and neurological disability. Brain imaging shows atrophy and a loss of myelin. Rarely, patients present later in life with psychomotor retardation and growth failure. Others have had initial normal development followed by a progressive loss of developmental milestones. Some patients have manifested spinocerebellar degeneration and other symptoms of motor dysfunction [27],... 

Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12. In the absence of normal B12 activation, homocystinuria results from a failure of normal vitamin B12 metabolism. Complementation analysis classifies defects in vitamin B12 metabolism into three groups cblC (most common), cblD and cblF. Most individuals become ill in the first few months or weeks of life with hypotonia, lethargy and growth failure. Optic atrophy and retinal changes can occur. Methylmalonate excretion is excessive, but less than in methylmalonyl-CoA mutase deficiency, and without ketoaciduria or metabolic acidosis. 

Lysinuric protein intolerance. Infants manifest growth failure, hepatosplenomegaly, vomiting, hypotonia, recurrent lethargy, coma, abdominal pain and, in rare instances,... 

Succinic semialdehyde dehydrogenase deficiency. Patients have mental retardation, cerebellar disease, and hypotonia. They excrete large amounts of both succinic semialdehyde and 4-hydroxybutyric acid. There is no known therapy. 

Patients with fucosidosis present with hypotonia, progressive mental retardation and motor deficits and also angiokeratomas in the skin, which resemble those in Fabry s disease. Mannosidosis patients show dysmorphic features, hepatosplenomegaly and mental retardation. 

Infantile, generalized cardiomegalic AMD, or Pompe s disease, usually becomes manifest in the first weeks or months of life, with failure to thrive, poor suck, generalized hypotonia and weakness, also termed floppy infant syndrome. Macroglossia is common, as is hepatomegaly, which, however, is rarely severe. There is massive cardio-megaly, with congestive heart failure. Weak respiratory muscles make these infants susceptible to pulmonary infection death usually occurs before the age of 1 year and invariably before the age of 2 years [6]. 

Fructose-1,6-bisphosphatase deficiency, first describ ed by Baker and Winegrad in 1970, has now been reported in approximately 30 cases. It is more common in women and is inherited as an autosomal recessive disorder. Initial manifestations are not strikingly dissimilar from those of glucose-6-phosphatase deficiency. Neonatal hypoglycemia is a common presenting feature, associated with profound metabolic acidosis, irritability or coma, apneic spells, dyspnea, tachycardia, hypotonia and moderate hepatomegaly. Lactate, alanine, uric acid and ketone bodies are elevated in the blood and urine [11]. The enzyme is deficient in liver, kidney, jejunum and leukocytes. Muscle fructose-1,6-bisphosphatase activity is normal. 

Defects of the Krebs cycle. Fumarase deficiency was reported in children with mitochondrial encephalomyop-athy. Usually, there is developmental delay since early infancy, microcephaly, hypotonia and cerebral atrophy, with death in infancy or early childhood. The laboratory hallmark of the disease is the excretion of large amounts of fumaric acid and, to a lesser extent, succinic acid in the urine. The enzyme defect has been found in muscle, liver and cultured skin fibroblasts [16]. 

Choline acetyltransferase deficiency. The distinguishing clinical feature is sudden episodes of severe respiratory difficulty and oropharyngeal (bulbar) weakness leading to apnea (cessation of respiration) precipitated by infections, fever or excitement, or occurring even spontaneously. In some patients, the disease presents at birth with hypotonia... 

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