Search

Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking. We describe and analyze eye movements in patients with an inborn error of metabolism, and see whether they can serve as an additional clue in the diagnosis of particularly late-onset inborn errors of metabolism. Demographics, disease characteristics, and treatment data were collected. All patients underwent a standardized videotaped neurological examination and a video-oculography. Videos are included. We included 37 patients with 15 different inborn errors of metabolism, including 18 patients with a late-onset form. With the exception of vertical supranuclear gaze palsy in Niemann-Pick type C and external ophthalmolplegia in Kearns-Sayre syndrome, no relation was found between the type of eye movement disorder and the underlying metabolic disorder. Movement disorders were present in 29 patients (78%), psychiatric symptoms in 14 (38%), and cognitive deficits in 26 patients (70%). In 87% of the patients with late-onset disease, eye movement disorders were combined with one or more of these core symptoms. To conclude, eye movement disorders are present in different types of inborn errors of metabolism, but are often not specific to the underlying disorder. However, the combination of eye movement disorders with movement disorders, psychiatric symptoms, or cognitive deficits can serve as a diagnostic clue for an underlying late-onset inborn error of metabolism.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism (IEM) due to mutations in the CYP27A1 gene. The clinical picture ranges from being nearly asymptomatic in early childhood, up to severe disability at adult age. Infantile-onset diarrhea and juvenile-onset cataract are the earliest symptoms in childhood. In the current study, we evaluated the presence of autism spectrum disorder (ASD) in a large cohort of CTX patients. METHODS: We performed a retrospective patient file study in 77 genetically confirmed Dutch CTX patients to determine the frequency of ASD. In addition, we compared plasma cholestanol levels in CTX patients with and without a diagnosis of ASD and tried to establish a relation between CYP27A1 genotype and ASD. RESULTS: In our CTX cohort, 10 patients (13%; nine pediatric and one adult) with ASD were identified. At the time of diagnosis of ASD, most patients only exhibited symptoms of diarrhea and/or intellectual disability without signs of cataract or neurological symptoms. No correlation was found between the presence of ASD and the level of cholestanol or CYP27A1 genotype. The behavioral problems stabilized or improved after treatment initiation with chenodeoxycholic acid (CDCA) in all pediatric patients. CONCLUSIONS: We conclude that ASD is an early and probably underestimated frequent feature in CTX. Metabolic screening for CTX should be performed in patients with ASD when accompanied by diarrhea, intellectual disability, juvenile cataract, and/or neurological involvement. Early recognition allows for earlier initiation of specific treatment and will improve clinical outcome. Our results add CTX to the list of treatable IEMs associated with ASD.

Cerebrotendinous xanthomatosis (CTX) is an inborn error of bile acid synthesis in which hepatic conversion of cholesterol to cholic and chenodeoxycholic acids is impaired. Patients have abnormal bile alcohols in urine, normal to increased plasma cholesterol concentrations and increased concentrations of plasma cholestanol. Little is known about cholesterol precursors in CTX, however. We studied cholesterol and phytosterol profiles in two siblings with CTX during follow-up. While cholesterol concentrations were low in both patients, plasma cholestanol was 6-fold higher compared to control values. In addition, both siblings had a more than 100-fold increase in 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC). Lathosterol, lanosterol and sitosterol were increased in both patients while concentrations of desmosterol and campesterol were normal. In addition, plasma lathosterol/cholesterol ratios were significantly elevated. After treatment with chenodeoxycholate, both patients showed a marked decrease in cholestanol, 7DHC, 8DHC, lathosterol, lanosterol and sitosterol. In addition, the lathosterol/cholesterol ratio normalized, indicating that overall cholesterol synthesis was sufficiently suppressed. This study shows that elevated cholesterol precursors, other than cholestanol, can be a hallmark for CTX.

Background X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder. Male patients develop adrenocortical insufficiency (80 % before 18 years), a chronic myelopathy (adrenomyeloneuropathy (AMN); all in adulthood), or progressive cerebral demyelination (cerebral ALD; 40 % before 18 years). Cerebral ALD is treated with haematopoetic cell transplantation (HCT). It is unknown if AMN still develops in patients with X-ALD that underwent HCT for cerebral ALD in childhood. Patients and methods A retrospective observational study was performed by selecting all adult patients with X-ALD in our cohort that underwent HCT in childhood. Results This retrospective study found that three out of five patients in our cohort who underwent HCT in childhood developed signs of myelopathy in adulthood. Conclusion These data suggest that HCT for cerebral ALD in childhood does not prevent the onset of AMN in X-ALD in adulthood.

A reduced availability of methyl groups within the central nervous system can cause demyelination of the brain (Surtees et al 1991). Cobalamin is the essential cofactor for homocysteine 5-methyltetrahydrofolate methyltransferase and methylmalonyl-CoA mutase. Consequently, cobalamin deficiency results in elevation of homocysteine and methylmalonic acid (Stabler et al 1988). Monitoring of the concentrations of homocysteine and methylmalonic acid in CSF may be applied for examining the cobalamin status of the brain. Normal methylmalonic acid CSF concentrations have been established by Stabler et al (1991). To our knowledge normal homocysteine CSF values are not published