[source]
pmid = PMID:31251474
title = Identification of a novel splice site mutation in the SERAC1 gene responsible for the MEGDHEL syndrome
[diagnosis]
disease_id = OMIM:614739
disease_label = 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
[text]
The proband was the third male child of nonconsanguineous Caucasian healthy parents.
The first child was a healthy girl, and the second a boy with language delay.
The mother reported two spontaneous miscarriages. The patient was born at term following a pregnancy
without abnormalities detected on routine ultrasound, but marked by maternal anorexia. Birth weight
and height were 2,890 g (−1 SD) and 46.5 cm (−1.5 SD), respectively, and head circumference was 35 cm
(+0.5 SD), with Apgar scores of 10 at 1 and 5 min. The first reported clinical manifestations were a
failure to thrive from 5 months old, with developmental delay and hypotonia. At 8 months old, he was
hospitalized for the follow-up of a convulsive encephalopathy. He had an episode of hypoglycemia
(0.36 g/L, 2 mmol/L) under fasting conditions, with lactic acidosis (6.7 mmol/L). After feeding every 4 hr,
there was a rapid recovery of the weight curve and changes in behavior, with a more active state.
A CT-scan (computed tomography) of the brain showed hypodensities of the basal ganglia.

At 1 year of age, a deltoid muscle biopsy was performed due to suspicion of a mitochondrial disease,
but showed nonspecific changes (diffuse atrophy of type II fibers without ragged red fibers or decrease
of cytochrome c oxidase staining, Figure S1) without structural alteration of mitochondria in electronic
microscopy (data not shown). With the parents’ consent, blood was drawn for DNA extraction, and a skin
biopsy was performed for further investigations.

At 4 years old, he could hold his head but not sit, had no voluntary grip and did not speak.
Since he did not react to loud sounds, an automated otoacoustic emission test was performed and
confirmed hearing loss, with no reproducible response from the peripheral level. Ophthalmological
assessment showed bilateral optic atrophy. He presented with failure to thrive and microcephaly,
with a height of 98 cm (−2 SD), a weight of 11.380 kg (−3 SD), and a head circumference of 48 cm (−1.5 SD).
Clinical examination revealed major axial hypotonia and mild dystonia. Organic acid analysis in the
urine demonstrated increased excretion of both 3-methylglutaconic acid and 3-methylglutaric acid;
peaks were not quantified but ranged from 100 to 200 mmol/mol of creatinine (normal < 20 mmol/mol of
creatinine). Although this was a significant excretion, it was not enough to suspect a primary 3-MGA-uria
(usually > 400 mmol/mol of creatinine, Wortmann, Kluijtmans, Sequeira, Wevers, & Morava, 2014).
Brain MRI (Figure 1a–d) showed a major and diffuse cortical and subcortical atrophy affecting both the
infratentorial and supratentorial regions, bilateral abnormalities of the putamen and thalami with
hyperintense signals on the T2-, fluid attenuated recovery- and diffusion-weighted images, and
hypointense signals on the T1-weighted images consistent retrospectively with the Leigh-like syndrome.
Brain MR spectroscopy showed increased lactate, with high levels in the putamen, and
reduced N-acetyl-aspartate, a marker of neuronal loss.
At 7 years of age, because of a low weight (−2.5 SD) and feeding difficulties,
he underwent antireflux surgery combined with gastrostomy placement, and salivary gland botulinum
toxin injections for excessive salivation and drooling. It is worthy to note that a minor
hemophilia A was discovered at that time, which required replacement therapy.
At 8 years of age, he underwent general anesthesia for dental extraction and experienced severe
acute respiratory distress syndrome postoperatively. Brain MRI showed major systemic atrophy,
hyperintense T2 signals of the putamen and hyperintense T2 signals of the brain stem,
signing acute brain injury. He was extubated and passed away with no diagnosis.