Early diagnosis and treatment of neonatal medium-chain acyl-CoA dehydrogenase deficiency: Report of two siblings

Two siblings are reported who were syptomatic in the neonatal period. The first died suddenly at 4 days of age after regurgitating a meal. The postmortem examination showed steatosis of the liver, kidney and muscle. In the second, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was diagnosed at 3 days of age with muscular hypotonia, vomiting, hyperammonaemia and mild acidosis. Thus disorders of fatty acid oxidation should also be considered in newborns. The biochemical work up indicates that in neonates, analysis of serum medium-chain fatty acids and of acyl and free carnitine are more likely to lead to a diagnosis than determining dicarboxylic acids alone in urine. Long-term treatment was effective and monitored by the acyl/free carnitine ratio.An abstract relating the initial findings of this patient was published by Catzeflis C, Délèze G, Kuchler H, Spahr A, Schütz B, Bachmann C (1987) Helv Paediatr Acta 42:47     

Peripheral sensory-motor polyneuropathy,pigmentary retinopathy,and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency

An 11-month-old girl presented acute episodes of hypoglycaemia and hepatic encephalopathy reminiscent of Reye syndrome and 3-hydroxydicarboxylic aciduria. The patient showed peculiar clinical manifestations of severe sensory-motor neuropathy, pigmentary retinopathy, and cardiomyopathy. She died of cardiac failure. Pathological studies of peripheral nerve showed signs of axonal neuropathy and demyelination. Enzymatic studies in cultured fibroblasts showed a deficiency of mitochondrial long-chain 3-hydroxyacyl-CoA-dehydrogenase. Peripheral nerve involvement and retinal pigmentary degeneration have as yet not been described in patients with proven defects of mitochondrial -oxidation.Part of the data presented in this paper were presented in abstract form at Vth International Congress of Inborn Errors of Metabolism, Asilomar June 1–5, 1990, Pacific Grove, CA, USA     

Medium-chain acyl-CoA dehydrogenase deficiency does not correlate with apparent life-threatening events and the sudden infant death syndrome: results from phenylpropionate loading tests and DNA analysis

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of fatty acid metabolism and typically presents in early childhood as potentially fatal hypoketotic, hypoglycaemic crisis often associated with Reye-like symptoms. Re-investigations of cases of sudden infant death syndrome (SIDS) have revealed in some instances a deficiency of MCAD, suggesting that this metabolic disorder may lead to sudden infant death without prior clinical symptoms. In the present study, we examined 142 infants who had suffered from an apparent life-threatening event (ALTE) or were otherwise considered at risk for SIDS for MCAD deficiency by phenylpropionate loading. In no case excretion of phenylpropionylglycine, the hallmark of MCAD deficiency, was increased. In contrast, 3 out of 55 children with symptoms of metabolic disorders showed increased phenylpropionylglycine excretion, and in all three cases MCAD deficiency was confirmed by DNA analysis. In addition, we investigated 142 cases of sudden unexplained child death and 100 control subjects for the A985G mutation in the MCAD gene which is associated with about 98% of enzyme deficiencies. We found one case of heterozygosity each in the patient and control group. Our data indicate that MCAD deficiency is not a major cause of ALTE and, in agreement with results from similar studies in other countries, its frequency is not increased in children who died of SIDS.     

精氨酰琥珀酸尿症导致新生儿死亡1例报告

目的报道1例早发型精氨酰琥珀酸尿症病例。方法女性患儿,于出生第2天发病,入院后经临床及实验室检查、基因检测获得诊断。结果患儿血氨显著增高,肝功能异常,伴代谢性酸中毒,血钾、血钙降低。血液瓜氨酸显著增高(1 098.12μmol/L)、精氨酸降低,尿乳清酸、尿嘧啶、精氨酰琥珀酸显著增高。经精氨酸支持、低蛋白饮食治疗无效,病情进行性加重,于生后23 d死亡。基因分析证实精氨酰琥珀酸裂解酶ASL基因存在c.544CT(p.R182X)和c.706CT(p.R236W)复合杂合突变,父母各携带1个杂合突变。结论此例为国内首次报道的早发型精氨酰琥珀酸尿症,死亡后获得确诊。精氨酰琥珀酸尿症是严重的遗传代谢疾病,临床诊断困难,生化特点为血瓜氨酸及尿精氨酰琥珀酸显著增高,ASL基因检测是诊断的关键。     

Acute fatty liver of pregnancy and neonatal long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency

Here we report a 7-month-old girl with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency with hypoketotic hypoglycemia; the mother had a history of acute fatty liver in a previous pregnancy leading to fetal death at 34 weeks of gestation. The misense mutation 1528G > C was detected in both alleles in the proband and in one allele in both parents. We emphasize that screening for fatty acid oxidation disorders and specifically LCHAD deficiency should be performed in newborns from mothers with hepatic complications during pregnancy such as acute fatty liver of pregnancy or severe or recurrent HELLP syndrome.     

The A985 to G mutation of the medium-chain acyl-CoA dehydrogenase gene and sudden infant death syndrome in Normandy

Medium-chain acyl-CoA dehydrogenase deficiency is the most common genetic defect of hepatic fatty acid oxidation. Clinical signs are somnolence and lethargy potentially leading to coma. Death occurs during the first attack in about 20% of cases, suggesting sudden infant death syndrome. A point mutation (adenine to guanine at position 985) in exon 11 of the medium-chain acyl-CoA dehydrogenase gene accounts for 90% of medium-chain acyl-CoA dehydrogenase deficiency-causing alleles. Such a high prevalence of a single mutation makes it possible to estimate the incidence of medium-chain acyl-CoA dehydrogenase deficiency in the general population and in sudden infant death syndrome. The study was performed by polymerase chain reaction amplification from blood spots on filter paper in 2000 randomly selected newborns (group I) and in 225 infants dead from sudden infant death syndrome (group II). Among 2000 newborns, 17 were found to be heterozygote for the G985 mutation. In group 11, one child was found with a single copy of the G985 mutation. So. the estimated frequency of the G985 mutation in the general population was 1/118 and the incidence of medium-chain acyl-CoA dehydrogenase deficiency was calculated as around 1/45 000 in Normandy.     

Is partial deletion of the complement C4 genes associated with sudden infant death?

The two C4 loci C4A and C4B in 61 cases of sudden infant death (SID), 93 living controls and 7 cases of infectious death were studied. In the SID group 13.1% showed deletion of the C4A gene, while 2.5% of the cases showed deletion of the C4B gene. This was not significantly different from neither the controls nor the infectious death group. We were not able to confirm that deletion of the C4B gene is associated with SID. However, in the SID group deletion of either the C4A or the C4B gene was associated with signs of infections prior to death (P=0.035). This observation may indicate that a proportion of SID victims are more vulnerable to infections than other infants.     

Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: Role of newborn screening

BACKGROUND:

The incidence of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) was estimated using the Canadian Paediatric Surveillance Program (CPSP) in Canada over a three-year period. Data regarding mutations associated with MCADD cases were collected wherever available.

METHODS:

Data were collected over a 36-month period using a monthly mailed questionnaire distributed through the CPSP to more than 2500 Canadian paediatricians, medical geneticists and paediatric pathologists.

RESULTS AND CONCLUSIONS:

During the three years of MCADD surveillance, 46 confirmed cases out of a total of 71 reported cases were found – an average of approximately 15 cases per year. This rate is lower than the initial estimate of approximately 30 cases per year of MCADD in Canada, based on the reported incidence of MCADD in the literature of approximately one in 10,000 to one in 20,000. All cases ascertained by newborn screening were asymptomatic. There were two deaths, both in jurisdictions without newborn screening for MCADD. The data support population-based newborn screening for MCADD.     

Deficiency of the α and β subunits of pyruvate dehydrogenase in a patient with lactic acidosis and unexpected sudden death

An infant with moderate muscular hypotonia and congenital lactic acidosis died suddenly at the age of 3 months. Autopsy revealed no abnormalities responsible for this unexpected death. Measurement of mitochondrial enzymes involved in energy production indicated a severely decreased total pyruvate dehydrogenase complex (PDHC) activity in muscle tissue (0.23 nmoles · min^–1 · mg protein^–1, control range 2.8–8.7) and moderately decreased PDHC activity in fibroblasts (0.27 nmoles · min^–1 · mg protein^–1, control range 0.37–2.32). The activity of the first component E₁ (pyruvate dehydrogenase) in muscle tissue was 10 times lower than that of controls (0.008 nmoles · min^–1 · mg protein^–1, control range 0.10–0.25). The activities of dihydrolipoyl dehydrogenase (E₃) and various other mitochondrial enzymes were normal. Immunochemical analysis in skeletal muscle tissue and fibroblasts demonstrated a decrease in the amount of the and subunits of E₁. The features of this patient are compared with those of other patients reported in the literature with immunochemically confirmed combined E₁ and deficiency.     

Combination of ABO blood group incompatibility and glucose-6-phosphate dehydrogenase deficiency: effect on hemolysis and neonatal hyperbilirubinemia

The incidence (%) of hyperbilirubinemia (serum bilirubin ≥257 μmol/l) was similar in neonates with a combination of ABO incompatibility and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (45%), with ABO incompatibility (54%) or G-6-PD deficiency (37%), alone (ns). Carboxyhemoglobin values, corrected for inspired CO, were similarly elevated in all three groups (0.87 ± 0.32%, 0.82 ± 0.29%, 0.76 ± 0.18%, respectively, ns), but correlated with bilirubin only in those with ABO incompatibility alone. ABO-incompatible/G-6-PD-deficient neonates, compared with those with either condition alone, are not at increased risk for hemolysis or hyperbilirubinemia.     

The G protein beta3 subunit 825C allele is associated with sudden infant death due to infection

AIM: To investigate the Gbeta3 subunit C825T polymorphism with regard to sudden unexpected infant death. The reported association between the Gbeta3s protein and increased immune cell function in humans makes this polymorphism highly interesting both with regard to sudden infant death syndrome (SIDS) and deleterious infectious disease. METHODS: The cases investigated in the present study consist of 250 SIDS cases, 38 cases of sudden unexpected infant death due to infection and 99 living infant controls. Typing of the C825T polymorphism was performed by real-time PCR with allele-specific probes and melting curve analyses. RESULTS: The cases of infectious death have a higher percentage of both the C allele (p=0.037 compared to the SIDS cases, p=0.022 compared to the controls) and the CC genotype (p=0.05 compared to the SIDS cases, p=0.016 compared to the controls). There were no differences between SIDS cases and controls. CONCLUSION: The observed association between the 825C allele and infectious death may indicate that the presence of the 825T allele exerts a protective effect towards serious infection, possibly through enhanced G protein signalling. The C allele, on the other hand, appears to represent a disadvantage in this regard.     

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目的探讨葡萄糖醛酸转移酶1A1(UGT1A1)基因G71R突变、葡萄糖-6-磷酸脱氢酶(G6PD)缺陷对新生儿生后前3d胆红素浓度的影响.方法测定81例新生儿脐血的G6PD活性及G71R基因型,分组比较生后前3d光疗前胆红素值的组间差异.用等位基因特异性寡核苷酸探针点杂交法(ASO)确定G71R基因型.结果在G71R野生型新生儿中,G6PD缺乏组与G6PD正常组相比,生后前3d胆红素值间无统计学差异.G6PD正常新生儿中,G71R突变纯合子或杂合子的新生儿生后前3d胆红素浓度与G71R正常野生型新生儿相比无统计学差异.G6PD缺陷新生儿中,同时合并有G71R突变纯合子或杂合子的新生儿组生后第2天、第3天胆红素浓度高于G71R正常野生型新生儿组.结论G6PD缺乏与G71R基因突变并存加重新生儿黄疸程度.     

Microcephaly,epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease‐causing homozygous mutations were identified in the immediate early response‐3 interacting protein‐1 (IER3IP1) gene. We report here an affected male born to a non‐consanguineous couple who was noted to have insulin‐requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti‐epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next‐generation sequencing approaches—such as exome sequencing reported here—may be an efficient means of uncovering a diagnosis in future cases.     

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??Objective To identify variables that might interfere with near final height??NFH?? of patients with congenital adrenal hyperplasia??CAH?? due to classic 21-hydroxylase deficiency??21-OHD??. Methods Eight-two patients with CAH due to classic 21-OHD achieved the NFH were followed up from March 1989 to May 2015 in Child Growth Center of the First Affiliated Hospital of SUN Yat-sen University. The NFH were compared with the standard height for the population and the target height??TH????and associated factors were analyzed. Results Eighty-two patients were followed up for approximately 10.6 yrs??0.5 to 25.5 yrs??. NFH SDS??-1.9±1.1?? was significantly lower than the normal population??P??0.001??. The treated group was significantly taller than the untreated group??P??0.01????early diagnosis group appeared to be taller than those with late diagnosis??P??0.019??. A better height outcome was observed in patients with advantage in TH??good compliance??and low HC dose by multivariate Cox regression analysis in 62 treatment patients. NFH and HC dose were negatively correlated??r??-0.23??P??0.078?? in treated group. For uncontrolled patients??patients with original HC does+letrozole had a better improvement than those receiving HC enhanced dose??P??0.064??. NFH SDS of patients with central precocious puberty who received GnRHa+letrozole was significantly higher than no-intervention group??P??0.005??. Conclusion Whether receiving treatment or not NFH of the classic 21-OHD children is below expectation??as compared with both the reference population and the target height??and is even lower in non-treatment group. Early diagnosis??early treatment??good compliance and lower dose of HC have a major impact on 21-OHD NFH. Associated adjuvant therapy of inhibiting bone maturation can somewhat improve NFH.     

κ light chain — myeloma associated with adult Fanconi syndrome: Response of the nephropathy to treatment of myeloma

The association of Bence Jones proteinuria with adult Fanconi syndrome has been reported in a small number of patients. The nephropathy and the Bence Jones proteinuria often precede by several years the diagnosis of frank myeloma. A 39-year-old woman developed renal glucosuria 2.5 years prior to the diagnosis of a plasma cell disease characterized by k Bence Jones proteinuria, osteolytic lesions, and histologically proven plasmacytomas. Serum phosphorus of 1.1–2.1 mg/dl and uric acid of 1.3–1.6 mg/dl were compatible with Fanconi syndrome. Glucosuria was constantly present, while the glucose tolerance test was normal. Urinary β₂ microglobulin (β₂M) excretion was up to 135 mg/24 hours (normal less than 0.14 mg), indicating failure of tubular absorption of this protein. Amino-aciduria was noted. The patient's myeloma responded to irradiation followed by melphalan plus prednisone and vincristine; the result was a marked reduction of the Bence Jones proteinuria. Some of the manifestations of the Fanconi syndrome disappeared, while the others were markedly reduced; this included disappearance of the glucosuria, elevation of the serum phosphorus and uric acid to normal, decrease of the urinary amino acid excretion to the normal range in 11 of the 14 amino acids tested, and decrease in the β₂ M excretion to 5.4 mg/24 hours. The response of the Fanconi syndrome to the treatment of myeloma supports the view that the nephropathy is due to the myeloma process, probably through renal tubular injury induced by Bence Jones proteinuria.