Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
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Alpers syndrome was not clearly defined until the link between brain and liver disease was described. Alpers syndrome can now be clearly established as a disorder of oxidative metabolism related to mitochondrial dysfunction, and in most instances with an autosomal mode of inheritance. The symptoms and signs are discussed. The illness occurs in the first years of life with the sudden onset of intractable seizures associated with developmental delay, hypotonia, ataxia, cortical blindness, and hepatic failure, and death occurs within a short time. Treating the seizures with valproic acid can cause the rapid onset of liver failure and must be avoided. To establish a definite diagnosis, liver and muscle biopsies may be needed. The former shows bile duct proliferation with the evidence of cirrhosis, and the latter may support the involvement of the mitochondrial respiratory chain if there are ragged-red fibres. Genetic studies can show an association with mitochondrial DNA depletion and mutations in the polymerase gene. Cytochrome c oxidase deficiency has been demonstrated in some patients. Useful diagnostic tests include liver function tests, lactic acid levels in the blood and cerebrospinal fluid, electroencephalograms, computed tomography, and magnetic resonance imaging. The differential diagnosis will be from other forms of neuronal degeneration and disorders of mitochondrial function. There is no specific treatment, which must await further research into causes.
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PMID:Alpers syndrome: progressive neuronal degeneration of children with liver disease. 1710 92

Glycogen storage disease type IV (GSD IV, or Andersen disease) is an autosomal recessive disorder due to the deficiency of 1,4-alpha-glucan branching enzyme (or glycogen branching enzyme, GBE1), resulting in an accumulation of amylopectin-like polysaccharide in muscle, liver, heart and central and peripheral nervous system. Typically, the presentation is in childhood with liver involvement up to cirrhosis. The neuromuscular form varies in onset (congenital, perinatal, juvenile and adult) and in severity. Congenital cases are rare, and fewer than 20 cases have been described and genetically determined so far. This form is characterized by polyhydramnios, neonatal hypotonia, and neuronal involvement; hepatopathy is uncommon, and the babies usually die between 4 weeks and 4 months of age. We report the case of an infant who presented severe hypotonia, dilatative cardiomyopathy, mild hepatopathy, and brain lateral ventricle haemorrhage, features consistent with the congenital form of GSD IV. He died at one month of life of cardiorespiratory failure. Muscle biopsy and heart and liver autoptic specimens showed many vacuoles filled with PAS-positive diastase-resistant materials. Electron-microscopic analysis showed mainly polyglucosan accumulations in all the tissues examined. Postmortem examination showed the presence of vacuolated neurons containing this abnormal polysaccharide. GBE1 biochemical activity was virtually absent in muscle and fibroblasts, and totally lacking in liver and heart as well as glycogen synthase activity. GBE1 gene sequence analysis revealed a novel homozygous nonsense mutation, p.E152X, in exon 4, correlating with the lack of enzyme activity and with the severe neonatal involvement. Our findings contribute to increasing the spectrum of mutation associated with congenital GSD IV.
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PMID:Neuropathological study of skeletal muscle, heart, liver, and brain in a neonatal form of glycogen storage disease type IV associated with a new mutation in GBE1 gene. 1935 89

Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogenicity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates.
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PMID:Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure. 2110 80

Glycogen storage disease type IV (GSD-IV), or Andersen disease, is a rare autosomal recessive disorder that results from the deficiency of glycogen branching enzyme (GBE). This in turn results in accumulation of abnormal glycogen molecules that have longer outer chains and fewer branch points. GSD-IV manifests in a wide spectrum, with variable phenotypes depending on the degree and type of tissues in which this abnormal glycogen accumulates. Typically, GSD-IV presents with rapidly progressive liver cirrhosis and death in early childhood. However, there is a severe congenital neuromuscular variant of GSD-IV that has been reported in the literature, with fewer than 20 patient cases thus far. We report an unusual case of GSD-IV neuromuscular variant in a late preterm female infant who was born to non-consanguineous healthy parents with previously healthy children. Prenatally, our patient was found to have decreased fetal movement and polyhydramnios warranting an early delivery. Postnatally, she had severe hypotonia and respiratory failure, with no hepatic or cardiac involvement. Extensive metabolic and neurological workup revealed no abnormalities. However, molecular analysis by whole-exome sequencing revealed two pathogenic variants in the GBE1 gene. Our patient was thus a compound heterozygote of the two pathogenic variants: one of these was inherited from the mother [p.L490WfsX5 (c.1468delC)], and the other pathogenic variant was a de novo change [p.E449X (c.1245G>T)]. As expected in GSD-IV, diffuse intracytoplasmic periodic acid-Schiff-positive, diastase-resistant inclusions were found in the cardiac myocytes, hepatocytes, and skeletal muscle fibers of our patient.
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PMID:Case of Neonatal Fatality from Neuromuscular Variant of Glycogen Storage Disease Type IV. 3031 Nov 41

Pediatric intractable autoimmune hepatitis is rare and may be responsible for acute liver failure. Mutations in the itchy E3 ubiquitin protein ligase (ITCH) gene (located on chromosome 20q11.22) can lead to a deficiency of the encoded protein, resulting in increased T-cell activity with lack of immune tolerance and manifestation of a complex systemic autoimmune disease. A 1-year-old girl of consanguineous parents received a liver transplant (LT) because of acute liver failure attributed to a drug-induced hypereosinophilic syndrome with positive liver-kidney-mikrosome-2 antibodies. Notable findings were syndromic features, dystrophy, short stature, psychomotor retardation, and muscular hypotonia. Later, we saw corticosteroid-sensitive rejections as well as a systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). Histologically, liver cirrhosis with lobular inflammatory infiltrates, giant-cell hepatitis, and ductopenia was verified in chronic cholestasis. Shortly after a second LT, a comparable liver histology could be detected, and viral, bacterial, and mycotic infections deteriorated the general health condition. Because of refractory pancytopenia related to portal hypertension and hypersplenism, a posttransplant lymphoproliferative disorder was excluded. One year after the second LT, epidural and subdural bleeding occurred. Three months afterward, the girl died of sepsis. Postmortem, whole-exome sequencing revealed a homozygous mutation in the ITCH gene. A biallelic mutation in ITCH can cause a severe syndromic multisystem autoimmune disease with the above phenotypic characteristics and acute liver failure because of autoimmune hepatitis. This case reveals the importance of ubiquitin pathways for regulation of the immune system.
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PMID:Mutation in ITCH Gene Can Cause Syndromic Multisystem Autoimmune Disease With Acute Liver Failure. 3070 42


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