Hyperinsulinism-hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease characterized by recurrent hypoglycemia and persistent mild elevation of plasma ammonia. HI/HA syndrome is one of the more common forms of congenital hyperinsulinism (CHI), caused by activating mutations within the GLUD1 gene that encodes the mitochondrial enzyme glutamate dehydrogenase (GDH). We report here on monozygotic twin girls presented with fasting- and protein-induced hypoglycemia and mild persistent hyperammonemia. Genetic analysis revealed that both girls were heterozygous for a novel missense mutation within exon 11 [c.1499A>T, p.(R443W)] of the GLUD1 gene. Despite early treatment with diazoxide and a low protein diet, they both developed non-hypoglycemic seizures in early childhood followed by cognitive impairment. In addition to their clinical course, a review of the literature on HI/HA syndrome is provided.
Background Hyperammonemic encephalopathy in newborns with urea cycle disorders and certain organic acidurias can cause severe brain injury, coma and death. Standard therapy includes protein restriction, nitrogen-scavenging drugs, prevention of catabolism and hemodialysis. Neuroprotective hypothermia as part of the treatment has been reported only 3 times. It has been suggested that mild systemic hypothermia can contribute to better neurological outcomes in hyperammonemic encephalopathy. However, the limited experience precludes accurate conclusions on safety and efficacy. Methods Whole body therapeutic hypothermia was included in the standard treatment of hyperammonemic encephalopathy in 4 neonates with urea cycle disorder or organic aciduria. Results Two patients survived the initial crisis. One patient has a developmental quotient of 0.8, while the other shows severe developmental delay. The cooling protocol had to be discontinued in 3 patients due to the otherwise untreatable complications (hypotension and hemorrhage). Conclusion The efficacy and safety of therapeutic hypothermia in the treatment of neonatal hyperammonemic encephalopathy depend on various factors, requiring further evaluation.
Background Infantile free sialic acid storage disease (ISSD) is a severe multisystemic disorder characterized by the accumulation of free sialic acid in lysosomes. Case presentation The patient presented prenatally with fetal ascites and large scrotal hernias, without pleural or pericardial effusion. During the infantile period, he was diagnosed with permanent isolated immunoglobulin G (IgG) hypogammaglobulinemia, which thus far has rarely been associated with ISSD. The analysis of the SLC17A5 gene revealed a novel homozygous 94 bp gene deletion. We further provide a detailed description of pre- and postnatal clinical and radiographic findings. Conclusions Fetal ascites could be the first sign of several lysosomal storage diseases (LSDs), including ISSD. The analysis of LSD gene panels is an effective approach to diagnosis in the case of non-specific symptoms and when specific biochemical tests are not easily available.
is a rare X-linked recessive disease. The MPS II is a hereditary metabolic disorder caused by accumulation of glycosaminoglycans (GAG) in organs and tissues due to mutations in the genes, which encode intralysosomal hydrolysis of macromolecules. Hunter syndrome is a progressive, multisystem disease. At the same time a child may have mental retardation and speech development delay, skeletal bone deformities, loss of vision, hearing loss. Patients and MethodsThe study included 17 boys aged from 2 to 12 years old with genetically confirmed Hunter syndrome. All patients underwent examination by otolaryngologist, also tympanometry, diagnostic nasopharyngolaryngoscopy, registration of otoacoustic emission, audiometry, cardiorespiratory monitoring were performed. ResultsThe accumulation of GAG leads to a gradual narrowing of the nasopharynx and larynx lumen, a thickening of the tongue and vocal folds, laryngeal cartilages deformation, an enlarged of pharyngeal, palatine and lingual tonsils.11 children (64.7%) had chronic inflammation of the nasal mucosa and pharyngeal tonsil with frequent exacerbations. Pharyngeal tonsil hypertrophy was detected in 10 patients (58.8%).14 children (82%) had a wide, thickened tongue. Hypertrophy of the tonsils was diagnosed in 8 children (47%).The voice had changed (hoarseness) in 16 children (94%). Deformation of the epiglottis was detected in 4 people (23.5%), tracheomalaciain 1 child (5.8%).Among the complications acute sinusitis and exudative otitis media were detectable in 52.9% of patients. 10 children (58.8%) had obstructive sleep apnea (OSA) syndrome, two of them (11.7%) had a severe degree of the disease, which was an indication for adenotonsillectomy. Hearing loss was found in 10 boys (58.8%).In most patients (82%) a combined pathology of the ear, throat and nose was detected, 2 children (11.7%) had only adenoid hypertrophy, and only 1 child (5.8%) did not have any pathology of ENT organs. Conclusion Functional disorders and diseases of the ear, throat and nose are found in most children with Hunter syndrome, which could be one of its early manifestations. An ENT specialist may suspect MPS type II according to the presence of an ENT pathology that is difficult to treat in a standard manner, combined with the pathology of other organs and systems.Early diagnosis and the possibility of enzyme replacement therapy can control the disease progression and avoid early disability.
We report clinical course and genotype of four patients with hepatocerebral form of MDS.Patients 1 and 2, daughters of consanguineous Roma parents, presented with liver failure at six and two days of life, respectively. The older sibling had lactic acidosis and progressive liver failure, without clear neurological involvement. Liver histology revealed gigantocellular hepatitis, fibrosis, cholestasis, hemosiderosis and steatosis. Working diagnosis was neonatal hemosiderosis. Despite the treatment, disease progressed to death at 40 days. Younger sibling had similar clinical course and MDS was suspected. Immunohistochemical staining of the deceased sibling's liver showed combined respiratory chain deficiency. Homozygous variant in the DGUOK gene in both patients confirmed the diagnosis. Despite cofactor/antioxidant treatment, patient 2 died at the age of two months.Patient 3 presented with recurrent nonketotic hypoglycemia, cholestasis and hypotonia at the age of two months. Liver disease was slowly progressive, with permanently elevated lactate and alanine. Histology showed gigantocellular hepatitis, fibrosis, cholestasis, hemosiderosis, polymorphous mitochondria and microvesicular steatosis. MDS was suspected, but immunohistochemical staining was uninformative. Due to end-stage liver disease, LTx was performed at the age of six months. Patient died in early postoperative period. Whole exome sequencing (WES) revealed biallelic mutations in the MPV17 gene.Patient 4 had intrauterine growth retardation, severe hypotonia and developmental delay since birth. Acute liver failure, presenting with ketotic hypoglycemia, lactic acidosis, hepatomegaly and coagulopathy, occurred at the age of four months. The individual additionally developed nystagmus. Brain MRI was normal. Liver biopsy showed steatosis and abnormal mitochondria. Immunohistochemistry and clearly decreased mtDNA copy number per nuclear genome in liver pointed to MDS. The disease progressed rapidly and patient died three weeks after admission. WES revealed two biallelic mutations in the POLG gene.Revealing genetic basis of liver failure due to MDS, with WGS as an important option, is pre-requisite to decision on LTx. It is also essential for genetic counseling and prenatal diagnosis in future pregnancies.
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