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Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms. In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease.

Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms. In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease. © 2016 The Author(s).

Mutations in several genes cause non-autoimmune diabetes, but numerous patients still have unclear genetic defects, hampering our understanding of the development of the disease and preventing pathogenesis-oriented treatment. We used whole-genome sequencing with linkage analysis to study a consanguineous family with early-onset antibody-negative diabetes and identified a novel deletion in PCBD1 (pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1 alpha), a gene that was recently proposed as a likely cause of diabetes. A subsequent reevaluation of patients with mild neonatal hyperphenylalaninemia due to mutations in PCBD1 from the BIODEF database identified three additional patients who had developed HNF1A-like diabetes in puberty, indicating early β-cell failure. We found that Pcbd1 is expressed in the developing pancreas of both mouse and Xenopus embryos from early specification onward showing colocalization with insulin. Importantly, a morpholino-mediated knockdown in Xenopus revealed that pcbd1 activity is required for the proper establishment of early pancreatic fate within the endoderm. We provide the first genetic evidence that PCBD1 mutations can cause early-onset non-autoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. This condition responds to and can be treated with oral drugs instead of insulin, which is important clinical information for these patients. Finally, patients at risk can be detected through a newborn screening for phenylketonuria.

Metabolic emergencies need to be recognized early, and the initiation of appropriate treatment without any delay determines the overall outcome. A significant proportion of patients with inborn errors of metabolism are at risk of developing a metabolic emergency at some time of their life, particularly those children affected by an inborn error of metabolism that manifests as an acute intoxication. These patients usually present as a neonate – typically after an initial symptom-free interval of some days – in an emergency situation. Treatment needs to be initiated immediately even without having arrived at the exact diagnosis.

Mitochondrial fatty acid oxidation disorders have been included in newborn screening programs worldwide since the implementation of tandem mass spectrometry-based screening. Disease-specific acylcarnitine profiles pinpoint at the respective enzyme defect; however, the diagnosis has invariably to be confirmed by enzyme assay and/or molecular analysis. Metabolic profiles can be normal in the anabolic state and, consequently, newborn screening may miss the diagnosis when performed outside the catabolic state on days 2 and 3 of life. Mitochondrial fatty acid oxidation disorders comprise four groups: (1) disorders of the entry of long-chain fatty acids into mitochondria, (2) intramitochondrial β-oxidation defects of long-chain fatty acids affecting membrane-bound enzymes, (3) β-oxidation defects of short- and medium-chain fatty acids affecting enzymes of the mitochondrial matrix, and (4) disorders of impaired electron transfer to the respiratory chain from mitochondrial β-oxidation. The main pathogenic mechanisms of fatty acid oxidation defects include toxic effects by accumulating acylcarnitine and acyl-CoA species and energy deficiency due to impaired fatty acid oxidation and ketone body formation. The respective disorders present with heterogeneous phenotypes. Before newborn screening (NBS) was introduced, the most common clinical presentations were hypoketotic hypoglycemia and sudden death, usually precipitated by an infection or fasting in the neonatal period or early childhood. In addition, severe cardiomyopathy and arrhythmias were leading clinical signs in the first months of life. Older children or adults may present with exercise- or illness-induced rhabdomyolysis. Patients can remain asymptomatic throughout life if they have mild defects and are not exposed to metabolic stress. Correlation of genotype and/or residual enzyme activity with disease phenotype has been reported for some defects, whereas in others additional disease modifiers are suspected. With newborn screening, disease incidence has significantly increased and the proportion of milder phenotypes has grown. Newborn screening greatly reduces the morbidity and mortality, though it does not eliminate early neonatal death in severe phenotypes. With respect to the heterogeneous clinical presentation, treatment needs to be tailored to the severity of the respective phenotype and the specific disorder.

Metabolic disorders that affect the lysosomal degradation of complex carbohydrates, lipids, and proteins are associated with a wide variety of clinical symptoms. At the severe end of the clinical spectrum, neurological symptoms are common and go along with significant brain pathology. The high abundance of sphingolipids in brain partially explains the major neurodegenerative effect of disturbed sphingolipid breakdown. In fact, sphingolipidoses frequently present with an involvement of the cerebral white matter. Other lysosomal disorders, in particular the neuronal ceroid lipofuscinoses (NCLs), primarily affect the cerebral grey matter. The NCLs share the lysosomal accumulation of autofluorescent storage material (lipofuscin) and often result from the disturbed degradation of hydrophobic proteins. The below table lists lysosomal storage diseases that are associated with neurodegeneration. At the milder end of the clinical spectrum, variable degrees of organ involvement exist, such as renal and cardiac disease in Fabry disease and hepatosplenomegaly with bone symtoms in gaucher disease. Neurological involvement is less prominent in these phenotypes.

The first subject described with a novel inborn error is almost invariably examined because of clinical disease, and it is only with the passage of time that the association between the biochemical and clinical phenotypes become better understood. This chapter will describe several biochemical phenotypes whose clinical relevance is now in question.