Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency.

BACKGROUND: This study aimed to describe the clinical, biochemical, and molecular characteristics of Chinese patients with holocarboxylase synthetase (HLCS) deficiency, and to investigate the mutation spectrum of HCLS deficiency as well as their potential correlation with phenotype. METHODS: A total of 28 patients with HLCS deficiency were enrolled between 2006 and 2021. Clinical and laboratory data were reviewed retrospectively from medical records. RESULTS: Among the 28 patients, six patients underwent newborn screening, of which only one was missed. Therefore, 23 patients were diagnosed because of disease onset. Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness, while only four cases remained asymptomatic nowadays. The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals. After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up. DNA sequencing revealed 12 known and 6 novel variants in the HLCS gene of patients. Among them, the variant of c.1522C > T was the most common. CONCLUSIONS: Our findings expanded the spectrum of phenotypes and genotypes for HLCS deficiency in Chinese populations and suggested that with timely biotin therapy, patients with HLCS deficiency showed low mortality and optimistic prognosis. Newborn screening is crucial for early diagnosis, treatment, and long-term outcomes.

Carnitine transporter and holocarboxylase synthetase deficiencies in The Faroe Islands.

Carnitine transporter deficiency (CTD) and holocarboxylase synthetase deficiency (HLCSD) are frequent in The Faroe Islands compared to other areas, and treatment is available for both disorders. In order to evaluate the feasibility of neonatal screening in The Faroe Islands we studied detection in the neonatal period by tandem mass spectrometry, carrier frequencies, clinical manifestations, and effect of treatment of CTD and HLCSD. We found 11 patients with CTD from five families and 8 patients with HLCSD from five families. The natural history of both disorders varied extensively among patients, ranging from patients who presumably had died from their disease to asymptomatic individuals. All symptomatic patients responded favourably to supplementation with L: -carnitine (in case of CTD) or biotin (in case of HLCSD), but only if treated early. Estimates of carrier frequency of about 1:20 for both disorders indicate that some enzyme-deficient individuals remain undiagnosed. Prospective and retrospective tandem mass spectrometry (MS/MS) analyses of carnitines from neonatally obtained filter-paper dried blood-spot samples (DBSS) uncovered 8 of 10 individuals with CTD when using both C(0) and C(2) as markers (current algorithm) and 10 of 10 when using only C(0) as marker. MS/MS analysis uncovered 5 of 6 patient with HLCSD. This is the first study to report successful neonatal MS/MS analysis for the diagnosis of HLCSD. We conclude that CTD and HLCSD are relatively frequent in The Faroe Islands and are associated with variable clinical manifestations, and that diagnosis by neonatal screening followed by early therapy will secure a good outcome.