Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China.

OBJECTIVES: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. METHODS: From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. RESULTS: Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). CONCLUSIONS: These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.

A systematic review of late-onset and very-late-onset multiple acyl-coenzyme A dehydrogenase deficiency: Cohort analysis and patient report from Taiwan.

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder with a dramatic clinical presentation. It was recently discovered that MADD may present at an advanced age. The clinical and laboratory data of an index patient and patients previously diagnosed at our institution were collected. A systematic review of previous studies retrieved from the PubMed, MEDLINE, and Embase databases published by February 1, 2020 was performed to collect patients with very-late-onset MADD (VLO-MADD, onset age > 60 years) globally and patients with late-onset MADD (LO-MADD, onset age < 60 years) in Taiwan. The clinical characteristics of the VLO-MADD patients were compared to those of LO-MADD patients. We report a patient with VLO-MADD who developed the first symptom at the age of 61 years. The patient presented with a Reye-like syndrome after taking aspirin for coronary artery disease. Repeated bouts of weakness were noted. Two variants of c.250 G > A (;) 419C > T were observed in the ETFDH gene. Another four patients with VLO-MADD were identified globally. Eighteen patients with LO-MADD were collected from our department and previously reported patients in Taiwan. There was no difference in the clinical symptoms (except for the onset age) or laboratory data between these two groups. Homozygous variants were not observed in any patients in the VLO-MADD group but were detected in 12 patients (66.6%) in the LO-MADD group (p = 0.014). Patients with MADD may first show symptoms in their 6th decade or beyond. The disease course may lead to erroneous diagnoses in this age group.

Late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD): case reports and epidemiology of ETFDH gene mutations.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a Chinese family of Southern Min origin with two affected siblings with late-onset riboflavin-responsive MADD due to a homozygous c.250G > A EFTDH mutation and review the genetic epidemiology of the c.250G > A mutation. CASE PRESENTATION: Both siblings presented with exercise-induced myalgia, progressive proximal muscle weakness and high levels of serum muscle enzymes and were initially diagnosed as polymyositis after a muscle biopsy. A repeat biopsy in one sibling subsequently showed features of lipid storage myopathy and genetic analysis identified a homozygous mutation (c.250G > A) in the ETFDH gene in both siblings and carriage of the same mutation by both parents. Glucocorticoid therapy led to improvement in muscle enzyme levels, but little change in muscle symptoms, and only after treatment with riboflavin was there marked improvement in exercise tolerance and muscle strength. The frequency and geographic distribution of the c.250G > A mutation were determined from a literature search for all previously reported cases of MADD with documented mutations. Our study found the c.250G > A mutation is the most common EFTDH mutation in riboflavin-responsive MADD (RR-MADD) and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries. CONCLUSIONS: Mutations in ETFDH should be screened for in individuals with lipid-storage myopathy to identify patients who are responsive to riboflavin. The c.250G > A mutation should be suspected particularly in individuals of southern Min Chinese background.

Newborn screening for glutaric aciduria type I in Victoria: treatment and outcome.

Between October 2001 and September 2007, a total number of 391,651 neonates were screened in Victoria using Tandem Mass Spectrometry and 6 newborns were diagnosed as having GA I, giving an incidence of 1:65,275 (CI: 1:29,988=1:177,861). Another patient was diagnosed through cascade screening of children born before the implementation of the expanded newborn screening program. Patients were treated by mild protein restriction (2-2.5 g/kg/day) and carnitine supplementation when well, focussing on the aggressive management of intercurrent illnesses (temporary cessation of protein intake, increase in calorie intake, IV carnitine, aggressive anti febrile and anti infectious treatment), including prophylactic admissions to hospital. Overall, our patients had 35 admissions to hospital, of which 15 were in the first year of life. None had a post infectious dystonic syndrome. Neuropsychological examinations revealed normal to high cognitive and gross motor function in all patients but one, with some deficiencies in fine motor activities and different levels of speech abnormalities in all patients. Since therapeutic approaches for GA I, although not uniform, are well established and have been documented to be effective, newborn screening for this disorder should prove justified. A therapeutic approach of dietary modification, IV carnitine and aggressive treatment of intercurrent illness seems to prevent the severe neurological complications of GA I. More in-depth consideration of speech and language function is necessary to document specific deficits in children with GA I and plan proactive interventions.