Increasing evidence suggests that the autism spectrum disorder (ASD) may be associated with inborn errors of metabolism, such as disorders of amino acid metabolism and transport phenylketonuria, ...homocystinuria, S-adenosylhomocysteine hydrolase deficiency, branched-chain α-keto acid dehydrogenase kinase deficiency, urea cycle disorders (UCD), Hartnup disease, organic acidurias (propionic aciduria, L-2 hydroxyglutaric aciduria), cholesterol biosynthesis defects (Smith-Lemli-Opitz syndrome), mitochondrial disorders (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes—MELAS syndrome), neurotransmitter disorders (succinic semialdehyde dehydrogenase deficiency), disorders of purine metabolism adenylosuccinate lyase (ADSL) deficiency, Lesch-Nyhan syndrome, cerebral creatine deficiency syndromes (CCDSs), disorders of folate transport and metabolism (cerebral folate deficiency, methylenetetrahydrofolate reductase deficiency), lysosomal storage disorders Sanfilippo syndrome, neuronal ceroid lipofuscinoses (NCL), Niemann-Pick disease type C, cerebrotendinous xanthomatosis (CTX), disorders of copper metabolism (Wilson disease), disorders of haem biosynthesis acute intermittent porphyria (AIP) and brain iron accumulation diseases. In this review, we briefly describe etiology, clinical presentation, and therapeutic principles, if they exist, for these conditions. Additionally, we suggest the primary and elective laboratory work-up for their successful early diagnosis.
During the last decade much important new information relating to the metabolic pathway from methionine to homocysteine has been gained. Interest has been stimulated by the discovery of two novel ...disorders, glycine N-methyltransferase deficiency and S-adenosylhomocysteine hydrolase deficiency. Another disorder in this pathway, methionine adenosyltransferase deficiency, has been increasingly detected, thanks to the expansion of newborn screening programmes by tandem mass spectrometry technology. These significant steps allow important insight into the pathogenesis of these three disorders, as well as into the mechanisms of damage to various organs (liver, brain, muscle) and point to the relevance of these disorders for crucial biological processes such as methylation, transsulfuration or carcinogenesis in mammals, the pathogenesis of numerous pathological conditions, in particular those associated with hyperhomocysteinaemia, the action and possible toxicity of some drugs or consequences of nutritional variations. This review summarizes current knowledge of three inherited disorders in this metabolic pathway and draws attention to their much broader significance for human health and understanding of important biological processes.
ABSTRACT
Objectives:
Sebelipase alfa is approved for treatment of lysosomal acid lipase deficiency (LAL‐D). This single‐arm, open‐label study (NCT02112994) evaluated sebelipase alfa efficacy and ...safety in patients with LAL‐D.
Methods:
Patients >8 months of age diagnosed with LAL‐D received sebelipase alfa 1.0 mg/kg by intravenous infusion every other week (qow) for up to 144 weeks. Dose escalation to 3.0 mg/kg qow and subsequently to 3.0 mg/kg weekly was permitted, per protocol; dose reductions for tolerability were permitted to 0.35 mg/kg qow. Descriptive statistical analyses were conducted.
Results:
Thirty‐one patients were enrolled and treated. Baseline median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were 63.5 and 65.5 U/L, respectively. Twenty‐eight patients completed 96 weeks of treatment, and 25 continued into the extended treatment period; 19 completed 144 weeks. From baseline to week 144, median ALT and AST levels changed by −42.0 and −22.0 U/L, respectively, median liver and spleen volumes changed from 1.4 to 1.3 and from 2.6 to 2.3 multiples of normal, respectively, median low‐density lipoprotein cholesterol levels decreased by 52.6 mg/dL, and median high‐density lipoprotein cholesterol increased by 9.8 mg/dL. Liver biopsies showed mostly improved or stable histopathology at 48 and 96 weeks versus baseline. Infusion‐associated reactions were mild (n = 1) or moderate (n = 2). One patient (a candidate for liver transplant at baseline) discontinued treatment because of liver transplant (unrelated to treatment). Two patients tested positive for nonneutralizing, anti‐drug antibodies on 1 occasion each.
Conclusion:
Sebelipase alfa was well tolerated and resulted in sustained improvements in liver and lipid parameters.
This phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, which causes cirrhosis and severe dyslipidemia, showed that enzyme replacement lessened ...multiple disease-related hepatic and lipid abnormalities.
Lysosomal acid lipase deficiency (Online Mendelian Inheritance in Man number, 278000)
1
is an autosomal recessive storage disease that is caused by mutations in the
LIPA
gene.
2
In infants, progression of the disease (historically known as Wolman’s disease) is very rapid, with death typically occurring by 6 months of age.
2
In older patients, progression of the disease (historically known as cholesteryl ester storage disease) leads to cirrhosis and other complications in childhood or later in life.
3
Common features in infants, children, and adults include elevated serum aminotransferase levels, dyslipidemia, hepatomegaly, liver fibrosis, and cirrhosis.
3
–
5
Awareness of the disease is low, . . .
Background
Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency and in about 50 % the etiology remains unknown. Recently biallelic mutations in
NBAS
were identified as a ...new molecular cause of ALF with onset in infancy, leading to recurrent acute liver failure (RALF).
Methods
The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients’ fibroblasts.
Results
The phenotypic spectrum of NBAS deficiency ranges from isolated RALF to a multisystemic disease with short stature, skeletal dysplasia, immunological abnormalities, optic atrophy, and normal motor and cognitive development resembling SOPH syndrome. Liver crises are triggered by febrile infections; they become less frequent with age but are not restricted to childhood. Complete recovery is typical, but ALF crises can be fatal. Antipyretic therapy and induction of anabolism including glucose and parenteral lipids effectively ameliorates the course of liver crises. Patients’ fibroblasts showed an increased sensitivity to high temperature at protein and functional level and a disturbed tethering of vesicles, pointing at a defect of intracellular transport between the endoplasmic reticulum and Golgi.
Conclusions
Mutations in
NBAS
cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes. NBAS deficiency is the first disease related to a primary defect of retrograde transport. Identification of NBAS deficiency allows optimized therapy of liver crises and even prevention of further episodes.
Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is ...a continuously growing number of patients but a lack of systematic and quantitative analysis.
Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods.
One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH).
We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.
Background and aim
To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation.
Methods
Datasets of ...567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA,
n
= 164), propionic (PA,
n
= 144) and isovaleric aciduria (IVA,
n
= 83), and glutaric aciduria type 1 (GA1,
n
= 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO).
Results
Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days,
p
< 0.001, but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl
−
) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl
−
: 10 % versus 39 %,
p
= 0.002; GA1: 26 % versus 73 %,
p
< 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl
−
to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used.
Conclusions
NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl
−
. Huge diversity of therapeutic interventions hampers our understanding of optimal treatment.
Carnitine uptake defect (CUD) is a rare autosomal recessive disorder caused by pathogenic variants in the SLC22A5 gene, resulting in primary carnitine transporter (OCTN2) deficiency and disturbed ...fatty acid oxidation. Patients may present in infancy with hypoketotic hypoglycemia, metabolic crisis, muscle weakness, cardiomyopathy, or sudden death, while some may remain asymptomatic even if not treated. We present a patient detected by newborn screening (NBS) who harbored a previously unreported homozygous variant in the SLC22A5 gene. OCTN2 activity testing showed mild deficiency.
Acetyl‐CoA transporter 1 (AT‐1) is a transmembrane protein which regulates influx of acetyl‐CoA from the cytosol to the lumen of the endoplasmic reticulum and is therefore important for the ...posttranslational modification of numerous proteins. Pathological variants in the SLC33A1 gene coding for AT‐1 have been linked to a disorder called Huppke‐Brendel syndrome, which is characterized by congenital cataracts, hearing loss, severe developmental delay and early death. It has been described in eight patients so far, who all had the abovementioned symptoms together with low serum copper and ceruloplasmin concentrations. The link between AT‐1 and low ceruloplasmin concentrations is not clear, nor is the complex pathogenesis of the disease. Here we describe a further case of Huppke‐Brendel syndrome with a novel and truncating homozygous gene variant and provide novel biochemical data on N‐acetylated amino acids in cerebrospinal fluid (CSF) and plasma. Our results indicate that decreased levels of many N‐acetylated amino acids in CSF are a typical metabolic fingerprint for AT‐1 deficiency and are potential biomarkers for the defect. As acetyl‐CoA is an important substrate for protein acetylation, we performed N‐terminal proteomics, but found only minor effects on this particular protein modification. The acetyl‐CoA content in patient's fibroblasts was insignificantly decreased. Our data may help to better understand the mechanisms underlying the metabolic disturbances, the pathophysiology and the clinical phenotype of the disease.
Contactin-associated protein-like 2 (
CNTNAP2
) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic
CNTNAP2
loss ...has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (
n
= 2) and bi-allelic (
n
= 20)
CNTNAP2
variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (
n
= 21), moderate to profound intellectual disability (
n
= 17) and epilepsy (
n
= 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (
p
< 0.0001), epilepsy (
p
< 0.0001), hyporeflexia (
p
= 0.012), ASD (
p
= 0.009), language impairment (
p
= 0.020) and severe cognitive impairment (
p
= 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic
CNTNAP2
variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.
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