Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder characterized by a deficiency in BCKD, the mitochondrial enzyme complex responsible for oxidatively decarboxylating leucine, isoleucine, and valine (refer to Fig. 20.11). As a result, these branched-chain amino acids (BCAA) and their corresponding α-keto acids accumulate in the bloodstream, leading to a toxic effect that disrupts brain function. The symptoms of MSUD include feeding difficulties, vomiting, ketoacidosis, changes in muscle tone, neurologic problems that may result in coma (mainly due to elevated leucine levels), and the distinct odor of urine resembling maple syrup due to increased isoleucine levels. If left untreated, the disease is fatal, and delayed treatment can lead to intellectual disability.

1. MSUD is classified into a classic type and several variant forms. The most common type is the classic neonatal-onset form, where patients exhibit little to no BCKD activity in leukocytes or cultured skin fibroblasts. Infants with this form show symptoms within the first few days of life, and if not diagnosed and treated promptly, it is fatal within weeks. Intermediate forms have a higher level of enzyme activity (up to 30% of normal) and present milder symptoms that can manifest from infancy to adolescence. Rare thiamine-dependent variant of MSUD can be managed with high doses of thiamine.

2. Similar to phenylketonuria (PKU), prenatal diagnosis and newborn screening are available for MSUD. Most affected individuals are compound heterozygotes.

3. Treatment for MSUD involves a specialized synthetic formula devoid of BCAA, supplemented with controlled amounts of leucine, isoleucine, and valine to support normal growth and development without reaching toxic levels. It is crucial to carefully monitor leucine levels as its elevation causes neurologic damage. Early diagnosis and adherence to dietary treatment throughout life are vital for proper development. Individuals with MSUD are at risk of decompensation during periods of increased protein breakdown as BCAA serve as an important energy source during metabolic needs.

C. Albinism

Albinism encompasses a group of conditions characterized by a defect in tyrosine metabolism leading to decreased melanin production. This deficiency results in partial or complete absence of pigmentation in the skin, hair, and eyes. Albinism presents in various forms and can be inherited through autosomal recessive (primary mode), autosomal dominant, or X-linked modes. The most severe form, tyrosinase-negative oculocutaneous albinism (type 1 albinism), exhibits a complete lack of pigment in the hair, eyes, and skin (see Fig. 20.21). This condition is caused by an absent or defective tyrosinase enzyme that requires copper. In addition to hypopigmentation, affected individuals experience vision impairments and sensitivity to sunlight (photophobia). They are also at an increased risk of developing skin cancer.

D. Homocystinuria
Maple syrup urine disease (MSUD) is a rare (1:185,000), autosomalrecessive disorder in which there is a partial or complete deficiency in BCKD, the mitochondrial enzyme complex that oxidatively decarboxylates leucine, isoleucine, and valine (see Fig. 20.11). These BCAA and their corresponding α-keto acids accumulate in the blood, causing a toxic effect that interferes with brain functions. The disease is characterized by feeding problems, vomiting, ketoacidosis, changes in muscle tone, neurologic problems that can result in coma (primarily because of the rise in leucine), and a characteristic maple syrup–like odor of the urine because of the rise in isoleucine. If untreated, the disease is fatal. If treatment is delayed, intellectual disability results.
1.
Classification: MSUD includes a classic type and several variant forms. The classic, neonatal-onset form is the most common type of MSUD. Leukocytes or cultured skin fibroblasts from these patients show little or no BCKD activity. Infants with classic MSUD show symptoms within the first several days of life. If not diagnosed and treated, classic MSUD is lethal in the first weeks of life. Patients with intermediate forms have a higher level of enzyme activity (up to 30% of normal). The symptoms are milder and show an onset from infancy to adolescence. Patients with the rare thiamine-dependent variant of MSUD respond to large doses of this vitamin.
2.
Screening and diagnosis: As with PKU, prenatal diagnosis and newborn screening are available, and most affected individuals are compound heterozygotes.
3.
Treatment: MSUD is treated with a synthetic formula that is free of BCAA, supplemented with limited amounts of leucine, isoleucine, and valine to allow for normal growth and development without producing toxic levels. [Note: Elevated leucine is the cause of the neurologic damage in MSUD, and its level is carefully monitored.] Early diagnosis and lifelong dietary treatment are essential if the child with MSUD is to develop normally. [Note: BCAA are an important energy source in times of metabolic need, and individuals with MSUD are at risk of decompensation during periods of increased protein catabolism.]
C. Albinism
Albinism refers to a group of conditions in which a defect in tyrosine metabolism results in a deficiency in the production of melanin. These defects result in the partial or full absence of pigment from the skin, hair, and eyes. Albinism appears in different forms, and it may be inherited by one of several modes: autosomal recessive (primary mode), autosomal dominant, or X linked. Total absence of pigment from the hair, eyes, and skin (Fig. 20.21), tyrosinase-negative oculocutaneous albinism (type 1 albinism), results from an absent or defective copper-requiring tyrosinase. It is the most severe form of the condition. In addition to hypopigmentation, affected individuals have vision defects and photophobia (sunlight hurts their eyes). They are at increased risk for skin cancer.
D. Homocystinuria