Approach to diagnosis of metabolic diseases

Abstract

Inborn errors of metabolism are generally categorized as rare diseases. Their presentations are often so subtle and insidious as to cause daunting diagnostic challenges for even the most astute clinicians. Thus, irreversible morbidity and preventable mortality have been unavoidable until recent decades because of delayed diagnoses. This unfortunate circumstance has led to newborn screening programs worldwide for 40 or more hereditary metabolic disorders beginning with the dramatic improvements for patients with phenylketonuria in the 1960's. Increasingly sophisticated testing procedures such as tandem mass spectrometry and other multiplex technologies applied to dried blood spot specimens are now having greater impact without raising costs significantly. The advent of next generation sequencing methods is likely to stimulate further progress and lead to whole genome or exome sequencing as prenatal and neonatal screening expands further. With early diagnosis through screening and expedited therapies better outcomes are routinely possible, and even preventive therapies amounting to "cures" can be anticipated through research.

NMR-based newborn urine screening for optimized detection of inherited errors of metabolism

“…The metabolites are numbered as shown in Table S2. Most commonly, an IEM produces alterations for several metabolites where the “reference metabolites” listed in Table 1 are those required to unambiguously identify an IEM, according to the seminal work of Wevers 17 and others 18 . Yet, as many metabolites can show abnormal concentrations due to different IEMs, their specific range values (if available, e.g., from HMBD, Metagene) are reported in Table S2.…”

Differential Diagnostics of Inherited Metabolic Disorders in Newborns

“…Convulsion syndrome is typical for amino acid metabolism and urea cycle disorders, organic acidemias, gangliosidosis, pyruvate metabolism disorders, peroxisomal disorders, mitochondrial disorders, biotinidase deficiency, glycine encephalopathy, molybdenum cofactor deficiency, sulfite oxidase deficiency, disorders of creatine, purine and pyrimidine metabolism. These pathologies are accompanied by progressive deterioration of neonate clinical status (noted in all organs and systems of the body), including electroencephalographic, and neurosonographic indicators as well [10].…”

Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories

“…While the diagnosis of OAs remains challenging because of the low incidence of these disorders, as well as their variable and non-specific presentation, recent advances in diagnostic techniques, such as newborn screening by tandem mass spectrometry [ 11 ], which allow earlier identification, are encouraging. Screening of neonates for OAs and other inherited metabolic disorders offers the potential for early diagnosis and therapy [ 63 ]; however, newborn screening is not offered in all countries, and evidence that screening improves long-term outcomes is currently limited [ 1 , 14 , 50 , 63 , 69 ].…”

“…Other OAs cause typical biochemical changes identified through newborn screening and have different clinical implications. While hyperammonaemia is an important manifestation of PA, MMA and IVA, its clinical significance needs to be considered together with other abnormalities, such as acidosis, ketosis, and lactic acidaemia, as well as distinguishing it from the hyperammonaemia caused by urea cycle disorders (UCDs) [ 11 ], the main group of conditions from which OAs must be differentiated [ 3 , 12 , 13 ]. Not all patients with PA, MMA or IVA present with hyperammonaemia, but most develop it in the newborn period, and continue to have recurrent episodes of hyperammonaemia during metabolic decompensation [ 3 , 14 ].…”