A 20-week ultrasound of a female fetus showed severe ventriculomegaly. The mother was referred for genetic and metabolic evaluation. There was no significant prior family history of hydrocephalus, neurodevelopmental disorder, or infantile death.

Nontargeted carrier screening of the parents demonstrated that both were carriers for carnitine palmitoyltransferase (CPT-II) deficiency. Amniocentesis confirmed that the fetus was compound heterozygous for the familial mutations (c.1816_1817del/p.Val606Leufs*2 and c.110_111dupGC/p.S38fs*36), confirming a diagnosis of severe congenital CPT-II deficiency. The patient was delivered at 38 weeks’ gestation and was started immediately on metabolic supplementation, including intravenous high-dextrose infusion and orogastric tube feeds with 4g/kg triheptanoin and polycal therapy.

Postnatal brain MRI and MRS confirmed the presence of a Dandy–Walker malformation, severe hydrocephalus, cerebellar vermis hypoplasia, polymicrogyria, and thinning of the cortex and corpus callosum ( Fig. 36.1 ). There was no lactate peak on MRS. Echocardiogram, cardiac telemetry, and abdominal imaging remained normal during hospitalization.

Neonatal carnitine palmitoyltransferase type II deficiency. Brain MRI, sagittal T1 shows severe communicating hydrocephalus with cortical malformations and cerebellar hypoplasia.

Metabolic labs demonstrated only mild elevation of transaminases and ammonia that resolved within the first week of life. There was no hypoglycemia or elevation of creatinine phosphokinase (CPK). Initial plasma acylcarnitine profile at 24 hours of life demonstrated an elevated C16 level of 12.4 nmol/mL (nl <0.35 nmol/mL).

The triheptanoin dosage was increased to 7 g/kg mixed, combined with Vivonex-10 formula and Polycal after the first 24 hours of life, with gradual reintroduction of long-chain fats with walnut oil over 3 weeks. Plasma C16 levels decreased to 3 to 4 nmol/mL with treatment. After stabilization, a VP shunt was placed. The patient was ultimately discharged from the neonatal intensive care unit (NICU) at nine weeks of life.

Hydrocephalus can be seen in the congenital form of CPT-II deficiency, as well as cobalamin C deficiency, many nonmetabolic genetic disorders (e.g., L1CAM syndrome), and acquired conditions (preterm intraventricular hemorrhage).

Brain malformations including polymicrogyria can be seen in certain inborn errors of metabolism (IEMs) including congenital CPT-II deficiency, severe multiple acyl-CoA dehydrogenase deficiency, some mitochondrial disorders (e.g., fumarase deficiency), peroxisomal biogenic disorders (e.g., Zellweger spectrum), and disorders of O-mannosylation of alpha-dystroglycan (e.g., Walker-Warburg syndrome).

Corpus callosum abnormalities can be seen with pyruvate dehydrogenase complex deficiency, Smith-Lemli-Opitz syndrome, and glycine encephalopathy.

Dandy-Walker malformations have a large differential diagnosis, although rarely associated with IEMs. Cerebellar hypoplasia is characteristic of congenital disorder of glycosylation type 1A.