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Technically, the only inborn error of metabolism I know that is autosomal dominant is acute intermittent porphyria. Also, the only inborn of metabolism I know that is X-linked recessive is Lesch-Nyhan syndrome.
Most deleterious mutations are partial or complete loss-of-function (LOF) mutations; most of those can be functionally compensated for by the presence of a wild-type (normal) copy on the other chromosome and so are recessive. Genes on the non-pseudoautosomal parts of X or Y are effectively hemizygous in males and thus LOF mutations there will likely be dominant. Such LOF mutations in females may also be dominant, depending on whether mosaic expression (due to X-inactivation) results in the phenotype.
Metabolic presentations part 1: neonates
You are working in the Paediatric Emergency Department and are called in to see a neonate with a history of irritability and seizures. You enter the room and are told the following: “Emma is a 3 day old, term baby who has been refusing feeds and crying excessively. Her mother says she has been irritable since birth. There has been no history of fever or cough. At home she had seizure-like activity with tonic posturing”. When you examine her, you find an awake, extremely irritable baby with flexed upper limbs flexed, extended lower limbs and global hyperreflexia. She is not dysmorphic and has no cardiac murmurs, respiratory distress or abdominal organomegaly.
Babies cry (a lot!) and we all know that, however Emma is presenting some red flags: she’s irritable and has an acute onset of seizures, without any obvious trigger.
Urine turns black on standing (and alkalinisation)Black ochrontic pigmentation of cartilage & collagenous tissueHomogentisic acid oxidase deficiencyAutosomal recessive diseaseCongenital
Beadle and Tatum 1945 discovered (Nobel prize 1958)All biochemical processes in all organisms are under genetic controlBiochemical processes are resolvable into a series of stepwise reactionsEach biochemical reaction is under the ultimate control of a different single geneMutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction
Nonstandard Abbreviations and Acronyms
adenosine monophosphate–activated protein kinase
congenital disorders of glycosylation
cardiac magnetic resonance imaging
DnaJ heat shock protein family member C19
heat shock protein family
inborn errors of metabolism
lysosome-associated membrane protein-2
left ventricular noncompaction
myoclonic epilepsy with ragged red muscle fibers
Z-band alternatively spliced PDZ-motif protein
Considerations in Older Infants and Children
Older infants with inborn errors of metabolism may demonstrate paroxysmal stupor, lethargy, emesis, failure to thrive, or organomegaly. Neurologic findings of neurometabolic disorders are acquired macrocephaly or microcephaly (CNS storage, dysmyelination, atrophy), hypotonia, hypertonia/spasticity, seizures, or other movement disorders. General nonneurologic manifestations of neurometabolic disorders include skeletal abnormalities and coarse facial features (e.g., with muco-polysaccharidoses), macular or retinal changes (e.g., with leukodystrophies, poliodystrophies, mitochondrial disorders), corneal clouding (e.g., with Hurler's syndrome, galactosemia), skin changes (e.g., angiokeratomas in Fabry's disease), or hepatosplenomegaly (with various storage diseases Table 2 1 – 3).
Consistent features of metabolic disorders in toddlers and preschool-age children include stagnation or loss of cognitive milestones loss of expressive language skills progressive deficits in attention, focus, and concentration and other behavioral changes. The physician should attempt to make fundamental distinctions between primary-genetic and secondary-acquired causes of conditions that present as developmental delay or failure to thrive. Clues can be extracted through careful family, social, environmental, and nutritional history-taking. Syndromes with metabolic disturbances may lead to the identification of clinically recognizable genetic disorders. Referral to a geneticist often is indicated to further evaluate physical findings of primary genetic determinants.
Initial laboratory investigations for older children are the same as for infants. Infants and children presenting with acute metabolic decompensation precipitated by periods of prolonged fasting should be evaluated further for those organic acid, fatty acid oxidation, or peroxisomal disorders that are not detected by tandem mass spectrometry or certain regional neonatal screening programs.
Cerebrospinal fluid (CSF) may be helpful in the evaluation of certain metabolic disorders after neuroimaging studies and basic blood and urine analyses have been completed. Common CSF studies include cells (to rule out inflammatory disorders), glucose (plus plasma glucose to evaluate for blood-brain barrier or glucose transporter disorders), lactate (as a marker of energy metabolism or mitochondrial disorders), total protein, and quantitative amino acids. Nuclear magnetic resonance spectroscopy can provide a noninvasive, in vivo evaluation of proton-containing metabolites and can lead to the diagnosis of certain rare, but potentially treatable, neurometabolic disorders.10 Electron microscopic evaluation of a skin biopsy is a highly sensitive screening tool that provides valuable clues to stored membrane material or ultrastructural organelle changes.11
Table 4 lists some of the more common inborn errors of metabolism, classified by type of metabolic disorder. Such prototypical inborn errors of metabolism include PKU, ornithine transcarbamylase deficiency, methylmalonicaciduria, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, galactosemia, and Gaucher's disease.
Neuronal ceroid lipofuscinosis
Neuronal ceroid lipofuscinosis (NCL) refers to a group of conditions that affect the nervous system. Signs and symptoms vary widely between the forms but generally include a combination of dementia , vision loss, and epilepsy . Although the NCLs were historically classified according to their age of onset and clinical symptoms, the most recent classification system is primarily based on their underlying genetic cause. Most forms are inherited in an autosomal recessive manner however, autosomal dominant inheritance has been reported in one adult-onset form (neuronal ceroid lipofuscinosis 4B). Treatment options are limited to therapies that can help relieve some of the symptoms.  
Why are almost all inborn errors of metabolism autosomal recessive? - Biology
OBJECTIVE. Inborn errors of metabolism in children can be challenging to interpret because of the similarity of their appearances on imaging. There are important clues to the diagnosis based on clinical history, head circumference (e.g., macrocephaly), geographic distribution of lesions (e.g., subcortical vs deep white matter or frontal vs parietooccipital), and other imaging features (e.g., contrast enhancement, calcification, cysts, and cortical dysplasia).
CONCLUSION. In this article, we present an algorithm-based approach to diagnosing pediatric metabolic disease with a discussion of key imaging features.
Inborn errors of metabolism (IEM) comprise a large group of genetic defects with specific biochemical and molecular abnormalities. Most of these disorders are attributed to an enzyme deficiency in the metabolic pathway, including accumulation of substrate (with damage induced by storage or toxicity), or to a deficiency of a product or an essential metabolite. In the brain, these disorders may cause hypomyelination as a result of failure to form specific myelin proteins, delay in myelination due to an inadequate supply of myelin precursors or accumulation of substances toxic to oligodendroglia, demyelination with the loss of normally formed myelin and preservation of the axons, myelin vacuolation (wherein degenerating white matter [WM] is replaced by fluid and vacuolization), and secondary demyelination with the destruction of both axons and myelin . Most leukoencephalopathies have a genetic basis, are progressive, and often produce symmetric changes on brain MRI.
The imaging evaluation of IEM is met by multiple challenges. Multiple enzyme defects can cause the same or similar clinical disorders. Moreover, variable forms of WM diseases can be caused by the same enzyme defect with overlapping symptoms at various ages, which results in a complex radiologic picture of a disease that may have multiple primary and secondary features. A variety of classification systems for leukoencephalopathies have been used. Neuroradiologists largely rely on pattern recognition coupled with clinical information and laboratory data to suggest specific disorders. Yet, almost 60% of inherited WM diseases remain without a specific diagnosis [2, 3].
Common neurologic presentations among patients with inherited metabolic diseases include acute encephalopathy, chronic encephalopathy, myopathy, movement disorders, and behavioral abnormalities. Chronic encephalopathy, with developmental delay or psychomotor retardation, is the most common neurologic form encountered in patients with IEM. Seizures, visual failure, extrapyramidal abnormalities, and dementia generally occur early in the course of gray matter (GM) diseases. Diseases predominantly affecting cerebral WM tend to present as motor difficulties, with weakness and incoordination. Acute encephalopathy is a presenting feature of several IEM disorders, in addition to a variety of acquired medical or surgical conditions. In IEM, deterioration of consciousness often progresses rapidly and usually shows no focal neurologic deficits. Some of the clinical features that can help in narrowing the differential diagnosis include age of onset of symptoms, normal milestones before presentation, family history, seizure, ocular manifestations, and presence of organomegaly. Most IEM disorders are inherited in an autosomal-recessive (AR) pattern. Fewer diseases are inherited in an X-linked pattern.
It is imperative for the radiologist to be familiar with the imaging appearance of normal myelination progression. The myelination process starts during intrauterine life and continues after birth in an orderly timely manner, commencing in the brainstem with progression to the cerebellum and the cerebrum . A simplified general rule of myelination progression is that it proceeds from caudal to rostral, from central to peripheral, and from dorsal to ventral. Myelination is usually complete on T1-weighted images by age 1 year (between 8 and 12 months) and on T2-weighted images at age 2 years (between 18 and 24 months) [4, 5]. Changes caused by brain myelination are seen earlier on T1-weighted images than on T2-weighted images, possibly because of T1 shortening by the cholesterol and glycolipid components of the developing myelin sheaths [4, 5]. T2-hypoin-tense signal change is seen later with more advanced stages of myelination.
There are numerous diseases caused by IEM, rendering their assessment quite challenging ( Fig. 1 ). Furthermore, many acquired pathologic processes, including periventricular leukoencephalopathy, inflammatory and infectious processes, acquired metabolic disorders with nutritional deficiencies, and toxic injuries, can present with radiologic abnormalities that mimic radiologic changes similar to those associated with IEM. To narrow the differential diagnosis, the combining of clinical and laboratory data, whenever available, with the imaging features is important. Additionally, serial imaging helps to differentiate IEM mimickers, which tend to be stable or improve on follow-up imaging studies, in contrast to IEM disorders, which are typically progressive.
Fig. 1 —Chart of imaging findings. Single asterisk denotes patients with inborn errors of metabolism (IEM) with macrocephaly. Double asterisk denotes patients with IEM and enhancement. PVL = periventricular leukoencephalopathy, WM = white matter, PMD = Pelizaeus-Merzbacher disease, PMLD = Pelizaeus-Merzbacher-like disease, 18q–syndrome = 18q deletion syndrome, HABC = hypomyelination with atrophy of basal ganglia and cerebellum, X-ALD = X-linked adrenoleukodystrophy, MLD = metachromatic leukodystrophy, MELAS = mitochondrial encephalopathy, lactic acidosis, and strokelike episodes, MLC = megalencephalic leukoencephalopathy with subcortical cysts, CST = corticospinal tract, MSUD = maple syrup urine disease.
The first step in radiologic assessment of IEM requires assessment of whether there is involvement of WM or GM or both. Diseases with predominantly WM involvement can be differentiated into disorders causing hypomyelination versus other IEM disorders. Additional helpful imaging features include identifying any supratentorial lobar predominance (frontal or parietooccipital or diffuse) determining the presence of deep, subcortical, or diffuse WM involvement determining the presence of symmetric versus asymmetric involvement identifying patchy versus confluent WM changes and determining the presence of posterior fossa involvement (brainstem, cerebellum, and dentate nuclei). Some of the other helpful imaging features are contrast enhancement (X-linked adrenoleukodystrophy, Alexander disease, Krabbe disease, and Refsum disease), cortical malformation (Zellweger syndrome, congenital muscular dystrophy, and glutaric aciduria type 1), calcification (Aicardi-Gout-ières syndrome, Cockayne syndrome, Krabbe disease, end-stage mitochondrial disorders, and cystic leukoencephalopathy without megalencephaly), ischemic changes (cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy, mitochondrial encephalopathy with lactic acidosis and strokelike episodes [MELAS], and Fabry disease), enlarged Virchow-Robin spaces (mucopolysaccharidosis, congenital muscular dystrophy, and Lowe syndrome), and subcortical cysts (megalencephalic leukoencephalopathy with subcortical cysts and Aicardi-Goutières syndrome). MR spectroscopy (MRS) can sometimes help with the diagnosis by revealing characteristic peaks of accumulated substrates (e.g., N-acetyl aspartate [NAA] in Canavan disease) or by revealing anaerobic glycolysis with elevated lactate. Serial imaging studies are helpful in determining the delay in myelination, the stability of the WM abnormality (stable or progressive), and the directionality of the WM abnormality (centrifugal, centripetal, ventrodorsal, or dorsoventral).
Neurologic symptoms are the most prominent and common clinical problems associated with IEM disorders . The clinical presentation of patients can be categorized as those who present with chronic encephalopathy versus those who present with acute encephalopathy. In this article, we divide the pediatric IEM into four broad categories according to their clinical presentation and imaging features: hypomyelination disorders, leukoencephalopathies presenting with macrocrania, leukoencephalopathies presenting with chronic encephalopathy and normal head size, and leukoencephalopathies presenting with acute encephalopathy and normal head size (Table 1).
Aromatic L-amino acid decarboxylase
globus pallidus (pars externa)
The globus pallidus (pars interna)
Guanosine triphosphate cyclohydrolase-I
Hypokinetic rigid syndrome
Inborn errors of metabolism
Magnetic resonance imaging
Neurodegeneration with brain iron accumulation
Positron emission tomography
Pantothenate kinase- associated neurodegeneration
Substantia nigra compacta
Substantia nigra reticulata
Single-photon emission computed tomography
Young adult onset Parkinsonism disease
- Most forms of GSD can be managed effectively with dietary therapy (e.g., uncooked corn starch, glucose preparations) with the aim of preventing hypoglycemia and/or muscle symptoms
- Foods rich in fructose and galactose should be avoided in patients with GSD type I
- Enzyme replacement therapy is available for some forms of GSD
- A liver transplant may be required in the case of liverGSD that progress to liver cirrhosis and/or result in poor metabolic control.
- Cardiac involvement
- Severe conduction defects: pacemaker implantation
- Severe cardiomyopathy: heart transplantation (see “Therapy” in “ Hypertrophic cardiomyopathy ”)
Pathophysiological Basis of Acquired Disorders
The brain, heart, skeletal muscle, and liver depend on ketone bodies or on glucose for energy and for carbon chains to synthesize cellular proteins (see the images below). For infants as well as individuals with decreased sugar intake because of starvation or dietary choices, ketones are the preferred fuel and source of carbon chains. Nervous and muscle tissues preferentially oxidize ketones over fatty acids, glucose, or amino acids under normal conditions. [1, 2, 3, 4]
Ketone bodies are largely beta-hydroxybutyrate and acetoacetate. These are formed in the liver and kidneys from the breakdown of fatty acids and a few amino acids. The brains of adults who live on a high-carbohydrate diet lose the ability to synthesize the key enzymes needed to metabolize ketones. These include beta-hydroxybutyrate dehydrogenase and acetoacetyl coenzyme A (CoA) synthetase (see the image below). For the brain to resynthesize these enzymes to effective levels, starvation for 3-7 days or a high-fat diet is needed.
Neural tissue has far more metabolic activity than other tissues of the body. The brain comprises only a small percentage of total body weight—approximately 1.4 kg in an average 70-kg person—but uses 20% of the body's oxygen at rest. In addition, neurons (and glia) are constantly synthesizing a variety of neurotransmitters, proteins for axonal flow, and proteins and lipids for regeneration of synaptic vesicles and other components of membranes. Many of these chemicals are synthesized in the brain, in part or wholly from glucose or ketone bodies.
Nonglucose carbohydrates (eg, galactose, mannose, inositol) are clinically important in fetal and neonatal nutrition however, little is known about their metabolism in the neonate. Glucose and galactose increase postprandially and several other carbohydrates contained in milk do not. Brown et al, in their attempt to determine whether postprandial changes in plasma carbohydrate and sugar alcohol concentrations are affected by clinical variables such as postnatal age, milk type, feeding volume, or feeding duration in term newborns, found that galactose is almost cleared completely by the neonatal liver. This provides novel evidence of a marked difference in plasma galactose concentrations [Gal] between relatively younger and older neonates. 
Acute hypoglycemia, as in an alcoholic or a diabetic who has taken too much insulin, causes the brain to be deprived rapidly and abruptly of blood glucose after it has depended for a long time on glucose rather than ketones as its fuel. Beta-hydroxybutyrate dehydrogenase and acetoacetyl CoA synthetase activity in the brain is insufficient to enable the blood ketones to sustain the brain's metabolism. Without fuel to burn, the neural tissue cannot carry out the high level of metabolism needed to pump ions, fire messages, or transmit intercellular chemical messages, let alone repair itself. The groggy state of sudden memory loss (ie, disorientation) and other intellectual deficits that internists tend to call confusion sets in rapidly with acute hypoglycemia, followed just as rapidly by a downhill course into obtundation, coma, and death. If the average adult brain can withstand only 4-6 minutes of oxygen deprivation, it can withstand only about 40-45 minutes without fuel.
Most physicians, as medical students or interns, have had experience treating diabetic ketoacidosis. Although the experience tends to cast ketone bodies as toxins, they are not. The acidosis produced by ketone bodies is toxic and is the direct cause of the Kussmaul breathing typical of patients with diabetic ketoacidosis. Patients with diabetes in this state usually have had normal to elevated blood glucose for the previous days or weeks. Enough glucose enters the brain cells during this time to inhibit synthesis of beta-hydroxybutyrate dehydrogenase and acetoacetyl CoA synthetase.
Again, the ketone-utilizing enzymes in the brain are not working at effective levels. By the time frank ketoacidosis sets in, too little insulin is left for the blood glucose to be able to sustain the high metabolic activity of the brain. The ketone bodies accumulate but cannot provide energy or carbon for the brain. The hydrogen ion associated with the ketones also accumulates, thereby stimulating (or overstimulating) acid receptors in the floor of the fourth ventricle and interfering with reuptake of potassium in the renal tubules.
The coma of hyperosmolar diabetic disorder seems to be related directly to the addition of large concentrations of glucose in the serum, the cerebrospinal fluid (CSF), the extracellular fluid of the brain and, perhaps to some degree, the intracellular fluid as well. The cause of high concentrations of glucose in these patients but not of ketone bodies remains unknown. The lack of ketones probably explains the lack of acidosis. CSF concentrations of glucose mirror those of the serum with a delay of approximately 2 hours. Patients do not regain consciousness immediately when the blood glucose is lowered.