18.2 Inheritance Patterns, Consanguinity & Inborn Errors of Metabolism

Why Inheritance and Metabolism Matter on This Exam

This exam tests Mendelian genetics through pedigree-style reasoning and regional clinical context rather than abstract definitions alone. Parental consanguinity — common across many Arab Board patient populations — sharply increases autosomal recessive disease risk and is a recurring clue in metabolic-disease vignettes. The single highest-yield metabolic pattern is the well newborn who deteriorates after feeds begin; using ammonia, glucose, and acid-base status to triage among urea cycle defects, organic acidemias, and fatty acid oxidation disorders is what separates a passing from a failing answer.

Mendelian Inheritance Patterns

Understanding single-gene (Mendelian) inheritance patterns lets you predict recurrence risk from a family pedigree — a core skill tested through worked scenarios rather than definitions alone.

Autosomal Dominant (AD)

A single mutant allele on one of the 22 autosomes causes disease. Key pedigree features: the trait appears in every generation (vertical transmission), an affected parent has a 50% chance of passing the condition to each child regardless of the child's sex, and unaffected individuals do not transmit the trait (assuming full penetrance). Examples relevant to pediatrics include neurofibromatosis type 1, tuberous sclerosis, achondroplasia, and Marfan syndrome.

Worked example: A father with achondroplasia (heterozygous) and an unaffected mother have three children. Each pregnancy independently carries a 50% chance of an affected child — it is incorrect to assume that because one child is already affected, the next is more likely to be unaffected (each pregnancy is an independent Bernoulli trial).

Autosomal Recessive (AR)

Disease requires two mutant alleles, one from each parent. Typically both parents are unaffected carriers (heterozygotes). Key pedigree feature: the trait often appears to "skip generations" and clusters in siblings rather than appearing in parents. When both parents are carriers, each pregnancy has:

Most inborn errors of metabolism are autosomal recessive, which is why this pattern is the backbone of the metabolic-disease topic below.

X-Linked Recessive

The mutant gene sits on the X chromosome. Because males are hemizygous (only one X), a single mutant X-linked recessive allele is sufficient to cause disease in a male, while females typically need two mutant copies (or are carriers with mild/no expression, subject to X-inactivation effects). Classic pattern: a carrier mother (heterozygous, unaffected) has, per pregnancy, a 50% chance of an affected son, a 50% chance of a carrier daughter, and no father-to-son transmission (fathers give sons a Y chromosome, not an X). An affected father passes the mutant X to all daughters (obligate carriers) but to no sons. Examples: Duchenne muscular dystrophy, hemophilia A/B, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and X-linked forms of ornithine transcarbamylase (OTC) deficiency (see below).

Worked pedigree example: A mother is a known carrier for Duchenne muscular dystrophy (her brother is affected, confirming her carrier status). She and an unaffected husband plan a pregnancy. For each son, risk of being affected is 50%; for each daughter, risk of being a carrier is 50% and risk of being affected is negligible (would require the father to also carry/express the allele, which is not the case here).

Consanguinity and Autosomal Recessive Risk — Regionally Critical

Consanguinity (marriage between blood relatives, most commonly first cousins in this exam's patient populations) is common across many countries served by the Arab Board and substantially raises the probability that both parents inherited the same rare recessive allele from a shared ancestor — a phenomenon called identity by descent. For first-cousin unions, the coefficient of relationship is 1/8, meaning the couple shares, on average, one-eighth of their genes by descent; this raises the baseline risk of a rare autosomal recessive disorder in offspring several-fold above the general population baseline, and the relative risk increase is largest for very rare alleles (where the alternative — two unrelated carriers meeting by chance — is exceedingly unlikely).

Clinically, this means:

• A history of parental consanguinity should raise your index of suspicion for an autosomal recessive inborn error of metabolism, a recessive skeletal dysplasia, or a recessive form of hearing loss/blindness whenever a child presents with an unexplained multisystem or progressive illness.
• Recurrent unexplained neonatal deaths or a family history of early infant deaths in a consanguineous family is a strong exam clue pointing toward a recessive metabolic disease, not an isolated congenital anomaly.
• Genetic counseling for consanguineous couples should include a detailed three-generation pedigree and, when a specific recessive disorder is suspected or has occurred in the family, carrier testing before or early in a subsequent pregnancy.

Approach to Inborn Errors of Metabolism (IEM) in the Newborn/Infant

Most IEMs are individually rare but collectively common, and nearly all are inherited in an autosomal recessive pattern (with important X-linked exceptions, notably OTC deficiency). The unifying exam pattern is the well newborn who deteriorates after a symptom-free interval — typically once feeds (breast milk or formula, both of which contain protein and/or lactose) begin.

When to Suspect a Metabolic Disease

• Normal at birth, then poor feeding, vomiting, lethargy, hypotonia, or seizures after 24-72 hours (once feeding introduces the offending substrate)
• Unexplained/recurrent encephalopathy without a clear infectious or hypoxic cause, especially with a normal septic workup
• Unusual odor of urine or sweat (e.g., "maple syrup" odor in maple syrup urine disease, "musty" odor in phenylketonuria, "sweaty feet" odor in isovaleric acidemia)
• A history of parental consanguinity or a prior unexplained sibling death/illness in infancy
• Hepatomegaly, cataracts, or coarse facial features developing over time (more typical of storage disorders than acute intoxication-type IEMs, but still on the differential)

Newborn Screening and Phenylketonuria (PKU)

Phenylketonuria (PKU) and classic galactosemia are the two prototype amino-sugar disorders on newborn screening panels. PKU is caused by deficiency of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine; deficiency causes phenylalanine to accumulate to neurotoxic levels. It is the prototype disorder detected by newborn screening (a heel-stick blood spot obtained after feeding has begun, generally in the first days of life). Untreated PKU causes progressive intellectual disability, seizures, eczema, a characteristic musty odor, and hypopigmentation (fair hair/skin, from reduced tyrosine-derived melanin) — but because treatment (a phenylalanine-restricted diet, begun as soon as screening flags an elevated level) is highly effective at preventing these outcomes, PKU is the classic exam example of why universal newborn screening exists: the disease is asymptomatic at birth, screening catches it before irreversible damage occurs, and early dietary treatment produces a normal or near-normal outcome.

Galactosemia results from deficiency of galactose-1-phosphate uridyltransferase (GALT), blocking metabolism of galactose from lactose in breast milk or standard formula. Affected infants develop jaundice, vomiting, hepatomegaly, and hypoglycemia after milk feeds begin, and are at risk for E. coli sepsis in the neonatal period. Urine shows reducing substances (not glucose-specific) while blood glucose may be low. Treatment is immediate removal of lactose/galactose from the diet (soy or lactose-free formula); breastfeeding is contraindicated.

Urea Cycle Defects and Hyperammonemia

The urea cycle converts nitrogen waste from protein metabolism into urea for excretion; a block anywhere in this pathway causes ammonia to accumulate. Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect and the important exception to "most IEMs are autosomal recessive" — it is X-linked, so affected males present severely in the newborn period while carrier females may be asymptomatic or have milder, later-onset disease.

Clinical picture: a full-term newborn feeds well for the first 24-48 hours, then develops poor feeding, vomiting, lethargy progressing to coma, and seizures — closely mimicking neonatal sepsis, which is why sepsis and a urea cycle defect are frequently paired as a "do not miss the other diagnosis" exam scenario. The critical laboratory clue is markedly elevated serum ammonia in the setting of respiratory alkalosis (hyperammonemia directly stimulates the respiratory center, causing hyperventilation and a high pH with low carbon dioxide) — this is a key discriminator from an organic acidemia, which instead produces a metabolic acidosis with an elevated anion gap, often with ketosis.

Rapid Triage Table

Immediate Management Principles (Exam-Level)

When an IEM is suspected in a decompensating infant: stop protein intake (remove the metabolic substrate), provide intravenous glucose to halt catabolism (catabolic states worsen ammonia and organic acid production by breaking down endogenous protein), send critical labs (ammonia, blood gas, glucose, lactate, urine and plasma amino/organic acids) before results delay treatment, and involve a metabolic specialist urgently — ammonia in particular is directly neurotoxic, and the duration of hyperammonemic coma correlates with neurologic outcome, so rapid recognition and treatment are what the exam is really testing.