Multiple Carboxylase Deficiency

(1)

30.1 Clinical Features

and Laboratory Investigations Two inherited defects in biotin metabolism are known: holocarboxylase synthase deficiency and biotinidase deficiency, both autosomal recessive disorders. A rare cause of biotin dependency is a genetic defect in the transport of biotin. Alimentary biotin deficiency is exceptional and may, for instance, be related to parenteral nutrition with a formula deficient in biotin, short bowel syndrome, or hemodialysis without biotin supplementation. Excessive intake of avidin, an egg-white glycoprotein that binds specifi- cally and irreversibly to biotin, may also result in biotin deficiency. All lead to deficiency of multiple carboxylases: 3-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase, pyruvate carboxylase, and the two isoenzymes of acetyl-CoA carboxylase.

The characteristic manifestations of multiple carboxylase deficiency consist of skin disease and neurological abnormalities. The skin abnormalities are de- scribed as seborrheic or atopic dermatitis. They consist of nonspecific, patchy, maculopapular, scaly and erythematous eruptions; they occur especially in moist and periorificial areas. In more severe cases lichenification, crusting, and open lesions may occur, that may become infected by Candida. The hair is of- ten sparse and thin and partial or total alopecia may be present that can include the eyebrows and eyelash- es.

Onset of clinical symptoms in patients with holocarboxylase synthase deficiency is between a few hours after birth and the age of 2 years. Most patients present in the first days or weeks after birth, but others present with acute metabolic derangement later, in the 2nd year of life. The symptoms may be precipi- tated by catabolism or increased dietary protein intake. The most common symptoms include tachypnea, stridor, skin rash, feeding difficulties, vomiting, hypotonia, developmental delay, tremor, ataxia, seizures, irritability, lethargy, and coma. Alopecia oc- curs in some of the patients. Disorders of immune function have been observed with a decreased T-cell count. The disease generally leads to severe neurological damage or death if untreated.

The age at onset in patients with a biotinidase deficiency is usually later and more variable. Most patients with a profound biotinidase deficiency have cutaneous and neurological symptoms in infancy or

early childhood, but patients with a partial biotinidase deficiency may not develop symptoms until adolescence. However, asymptomatic adults, both with a partial and a profound biotinidase deficiency, have been detected. When patients present, the symptoms are essentially the same, independent of age, although older patients tend to have fewer symptoms.

Most patients present between the ages of 6 weeks and 18 months. Most have progressive encephalopathy, but some have episodes of acute deterioration.

The most common symptoms are skin rash, partial or complete alopecia, hypotonia, spasticity, developmental delay, seizures including infantile spasms, and sensorineural hearing loss. In many patients the seizures are difficult to control with antiepileptic medication. Less common features are keratocon- junctivitis, ataxia, fatigue, lethargy, tachypnea, apnea, laryngeal stridor, scotomas, and loss of vision due to optic atrophy. Some patients develop feeding difficulties, vomiting, diarrhea, hepatomegaly, splenomegaly, or coma. Immunological dysfunction may occur in acutely ill patients. Older patients often present with optic atrophy, sensorineural hearing loss, and gait problems; some of them have a mental retardation, but others are intellectually intact. Biotinidase deficiency generally leads to progressive clinical symptoms ending in severe neurological damage or death if untreated.

Laboratory findings in affected children include metabolic acidosis, mild hyperammonemia, and organic aciduria. Increased urinary excretion is usually found of 3-methylcrotonylglycine and 3-hydroxyiso- valerate reflecting methylcrotonyl-CoA carboxylase deficiency; 3-hydroxypropionate, propionylglycine, tiglylglycine, propionate, and methylcitrate reflecting propionyl-CoA carboxylase deficiency; and lactate, which likely reflects pyruvate carboxylase deficiency.

In holocarboxylase synthase deficiency the biochemical abnormalities tend to be more severe and complete than in biotinidase deficiency. However, in some patients with holocarboxylase synthase deficiency the biochemical abnormalities are only mild, rather suggesting biotinidase deficiency. In some children with biotinidase deficiency, urinary organic acids are normal at presentation.

The diagnosis of holocarboxylase synthase deficiency is confirmed by showing deficiency of 3- methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA

Multiple Carboxylase Deficiency

Chapter 30

030_Valk_MultipleCarboxy 08.04.2005 15:48 Uhr Seite 248

(2)

carboxylase in lymphocytes or fibroblasts in a medi- um with low biotin concentration. The enzyme activities remain severely deficient after in vitro preincubation with biotin. The diagnosis of biotinidase deficiency is confirmed by showing decreased or absent enzyme activity in serum, leukocytes, and fibroblasts.

In biotinidase deficiency and acquired biotin deficiency, carboxylase activities in lymphocytes are usually decreased but may also be normal, depending on the degree of biotin deficiency; the carboxylase activities increase significantly or normalize after in vitro preincubation with biotin. Plasma biotin concentration is usually below normal in symptomatic patients with biotinidase deficiency and in acquired biotin deficiency, but normal in holocarboxylase synthase deficiency. Prenatal diagnosis can be performed by enzyme assays in cultured chorionic villi and amniotic fluid cells.

30.2 Pathology

Reports on neuropathological findings are scarce.

The external appearance of the brain is usually normal. Ill-demarcated, partly necrotizing focal lesions are found in the white matter of the cerebral hemi- spheres, thalamus, hypothalamus, subthalamic nucleus, hippocampus, mammillary bodies, substantia ni- gra, red nucleus, oculomotor nuclei, periaqueductal gray matter in the midbrain, tegmentum of the pons, dorsomedial parts of the medulla oblongata, inferior olivary nucleus, deep cerebellar white matter, cerebellar nuclei, and the posterior, lateral, and anterior columns of the spinal cord. The lesions show rarefac- tion, microcavitation, sponginess, capillary prolifera- tion, and gliosis. Reactive astrocytes and foamy macrophages are present. Myelin is lost and neurons are relatively preserved. The lesions are similar to those observed in Leigh syndrome and thiamine deficiency.

Another striking finding is vacuolation and edema of white matter tracts, including parts of the corpus callosum, fornix, the central tegmental tracts in the pons, the decussation of the medial lemniscus, the su- perior cerebellar peduncles, the pyramids, and anteri- or columns of the spinal cord. Abnormalities involv- ing the lateral and posterior columns have also been reported. Myelin loss is seen with relatively less severe axonal loss. Defective myelination and gliosis of the cerebral and cerebellar white matter have also been reported. The optic nerves may display severe loss of myelinated fibers.

30.3 Pathogenetic Considerations

Biotin is an essential water-soluble vitamin and is the coenzyme for four carboxylases, propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl carboxylase, which are involved in the catabolism of several branched-chain amino acids, gluconeogenesis, and fatty acid synthe- sis. Each of the four carboxylases is synthesized in an inactive form called apocarboxylase and becomes en- zymatically active only when it is linked covalently to biotin; it is then called holocarboxylase. Holocar- boxylase synthase catalyzes the covalent binding of biotin to a lysine residue in the four biotin-dependent enzymes. Humans cannot synthesize biotin and therefore derive the vitamin from dietary sources or from recycling endogenous biotin. The carboxylases are degraded proteolytically to amino acids and bio- cytin (biotinyl-N-¥-lysine). Biocytin is then hy- drolyzed by biotinidase to lysine and free biotin, thereby recycling the vitamin for reutilization. Bio- tinidase is also necessary for liberating biotin from dietary protein-bound sources to its free, bioavailable form. Additionally, biotinidase has biotinyl trans- ferase activity, in which biotin from biocytin is trans- ferred to other proteins. The gene encoding holocar- boxylase synthase, HLCS, is located on chromosome 21q22.1. The gene encoding biotinidase, BTD, is locat- ed on chromosome 3p25.

The multiple carboxylase deficiencies are geneti- cally determined or acquired disorders of biotin metabolism and result in impaired activity of all four biotin-dependent carboxylases. There are two forms of inherited multiple carboxylase deficiency: holocarboxylase synthase deficiency and biotinidase deficiency. In holocarboxylase synthase deficiency, the carboxylases remain in their inactive apo-form. In biotinidase deficiency, endogenous biotin cannot be re- cycled and dietary protein-bound biotin cannot be released. Biocytin is lost in urine, leading to progressive biotin depletion. The clinical symptoms of holocarboxylase synthase deficiency and biotinidase deficiency overlap, but ophthalmological abnormalities and hearing loss have not been observed in holocarboxylase synthase deficiency. The symptomatology in holocarboxylase synthase deficiency tends to be of earlier onset and more severe than in biotinidase deficiency, although there is a major overlap. In biotinidase deficiency, the level of the residual enzyme activity correlates with the development of clinical and biochemical abnormalities. Most patients with profound biotinidase deficiency develop early signs of the disease. Patients with partial biotinidase deficiency may be healthy and develop symptoms only under conditions of infection or starvation. A special variant of the disease is related to decreased affinity of biotinidase for biocytin, the so-called Kmvariant

30.3 Pathogenetic Considerations 249 030_Valk_MultipleCarboxy 08.04.2005 15:48 Uhr Seite 249

(3)

with a reduced maximum reaction velocity and an elevated Kmof biotinidase for biocytin.

30.4 Therapy

Holocarboxylase synthase deficiency can often be treated effectively with pharmacological doses of biotin. The required dose of biotin is dependent on the severity of the enzyme defect and has to be assessed individually. With treatment the symptoms usually either disappear or improve and further deterioration can usually be prevented. An important problem is that delayed diagnosis leads to permanent damage that cannot be undone with treatment. Unfortunately, some patients show only a partial response to biotin or no response at all. Persistence and even progres- sion of the encephalopathy despite very high doses of biotin has been observed in some patients. It is likely that some defects in holocarboxylase synthase make it unresponsive to biotin supplementation.

The results of biotin treatment in biotinidase deficiency are even better. With treatment most or all symptoms disappear and further deterioration can be prevented. The only problem is that damage already acquired may not be entirely reversible. In particular auditory and visual deficits, but also intellectual im- pairment and motor deficits may persist in spite of treatment. For this reason, neonatal screening for biotinidase deficiency has been instituted in many countries. Early diagnosis and treatment prevent the onset of symptoms. Patients with a partial biotinidase deficiency and the biotinidase Kmvariant should also be treated with biotin, especially as biotin has no known harmful effects.

Prenatal diagnosis is possible. If holocarboxylase synthase deficiency is detected, antenatal treatment can be started by treating the mother with biotin, pre- venting acute neonatal symptoms. Intrauterine treatment is not necessary for biotinidase deficiency, because of the later onset of symptoms.

30.5 Magnetic Resonance Imaging

CT of the brain may show basal ganglia calcification in untreated multiple carboxylase deficiency. Diffuse hypodensity of the cerebral white matter within the neonatal period with disappearance of the hypodensity after many months of treatment has been reported. The problem is that the cerebral white matter is al- ways hypodense in neonates due to lack of myelin, and that disappearance of the hypodensity with on- going myelination is a normal phenomenon. The white matter does, however, look more hypodense than normal and mildly swollen on the CT pictures

published, suggesting diffuse white matter vacuolation or edema.

MRI shows variable abnormalities in untreated multiple carboxylase deficiency, including delayed myelination, diffuse cerebral white matter signal ab- normality and swelling, more patchy cerebral white matter abnormalities, and cerebral atrophy (Figs. 30.1 and 30.2). The white matter abnormalities and cerebral atrophy are at least partially reversible with treatment. These imaging abnormalities have a low diag- nostic specificity. Signal abnormalities in central gray matter structures, brain stem, and spinal cord have also been reported, suggestive of a Leigh-like disease.

These may be entirely or partially reversible with treatment. With Leigh-like abnormalities present on MRI, the possibility of multiple carboxylase deficiency should be considered.

One paper by Wiznitzer and Bangert (2003) reports signal changes in the spinal cord over its entire length in a patient with clinical ataxia and spastic paraparesis. The abnormalities disappeared with treatment.

Chapter 30 Multiple Carboxylase Deficiency 250

Fig. 30.1. A 1-year-old girl just diagnosed with biotinidase de- ficiency. The child presented with psychomotor retardation, spastic quadriplegia, and a severe seizure disorder. The MRI shows a severe delay in myelination. The white matter of the centrum semiovale looks spongy with many tiny cysts, which could also be enlarged perivascular spaces. The subarachnoid spaces are mildly enlarged, compatible with mild cerebral atrophy. Courtesy of Dr. Z. Patay, Department of Radiology, and Dr. P.T. Ozand, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

䊳

Fig. 30.2. A 1-year-old boy just diagnosed with biotinidase deficiency. He presented with an acute metabolic crisis. The MRI shows delayed myelination and mildly enlarged subarachnoid spaces.There are more prominent signal abnormalities in the deep parietal white matter, where the white matter also looks spongy with many tiny cysts, possibly enlarged perivascular spaces. Courtesy of Dr. Z. Patay, Department of Radiology, and Dr. P.T. Ozand, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

䊳

030_Valk_MultipleCarboxy 08.04.2005 15:48 Uhr Seite 250

(4)

30.5 Magnetic Resonance Imaging 251 030_Valk_MultipleCarboxy 08.04.2005 15:48 Uhr Seite 251