Zellweger Syndrome

A disorder characterized by the congenital absence of functioning peroxisomes (the cellular structures that are responsible for the elimination of toxic substances) resulting in a cerebrohepatorenal syndrome. The disease affects brain development, particularly nerve myelination. Most important features include hepatomegaly, polycystic kidney disease, visual disturbances, and high plasma levels of iron and copper. Other clinical features include muscular hypotonia already noticeable at birth, mental retardation, seizures, coagulopathy, and dysphagia with recurrent aspiration. Congenital heart defects have been described. Life expectancy is approximately 6 months.

Cerebro-Hepato-Renal Syndrome.

Autosomal recessive. Gender distribution is equal. Gene map locus is at 7q11.23. There are several phenotypes that are caused by mutations in any of the several different genes involved in peroxisome biogenesis.

Thought to be a group of disorders of peroxisomal biogenesis in which the primary defect involves the import mechanisms of matrix enzymes. This results in production of “ghost” organelles that consist of an empty membrane.

Clinically evocated by aberrant development of the skull, face, ears, eyes, hands, and feet, polycystic kidneys, and intrahepatic biliary dysgenesis. Confirmed by biochemical studies involving blood cells and fibroblasts. The presence of high levels of iron and copper in the blood is characteristic of this disease. There are specific and sensitive biochemical assays of peroxisomal function available, including a decreased dihydroxyacetone phosphate-adenosine triphosphate (DHAP-AT) activity and an increase in very-long-chain fatty acids. Serum iron and iron-binding capacity are high and peroxisomes are abnormal.

These infants are subject to early death within a few months (mean = 12.5 weeks). The clinical features involve head (high forehead, flat facies, cleft palate, micrognathia, characteristic eye changes, including mongoloid slant, hypertelorism, Brushfield spots, cataracts, pigmentary retinopathy, and optic nerve dysplasia) and central nervous system (CNS) (seizures, absent Moro reflex). Prenatal growth failure, failure to thrive, poor suck, muscular hypotonia, mental retardation, areflexia, deafness and congenital heart defects (patent ductus arteriosus, septal defects, aortic abnormalities) can be observed. Others features include apneas, polycystic kidneys, cryptorchidism, hepatomegaly, jaundice, mitochondrial abnormalities, liver cirrhosis, camptodactyly, talipes equinovarus, and stippled chondral calcification.

Full assessment of the disorder and the extent of involvement of neurological, cardiac, respiratory, and hepatic systems. It is recommended to obtain consultation with appropriate specialties, and investigations. Because preoperative fasting is not tolerated by the infant, an endocrine consultation may be required to discuss appropriate intravenous fluids and supplementation. Complete assessment of coagulation. Correct hypoprothrombinemia.

The usually severe neurological problems may require the insertion of a gastrostomy tube for palliative feeding, which can often be achieved with an eutectic mixture of local anesthetics and infiltration of local anesthesia. The presence of muscular hypotonia must be considered. Ketamine is a useful supplement when general anesthesia not recommended. If anesthesia must be given, considerations include the possibility of a difficult intubation, poor protection of the airway and recurrent pulmonary aspiration, tendency to apnea postoperatively, and complicating factors such as cardiac and hepatic disease.

If anesthesia must be performed, consideration must be given to interactions of the drugs with preexisting hepatic and renal dysfunction. The use of opiates must be done carefully because of severe neurological defects and tendency to apnea. Prophylactic antibiotics in case of cardiopathy as indicated.

(An overview table can be found under Leukodystrophies: Overview)

Alexander Syndrome: A degenerative and progressive disorder of the CNS caused by leukodystrophy. Affects mainly males and usually begins at about 6 months of age. Symptoms include mental and physical retardation, enlargement of the brain and head, spasticity (arms and legs), and seizures.

Canavan Syndrome: A progressive leukodystrophy caused by spongy degeneration of the central nervous system. It is uniformly fatal within 18 months after onset of symptoms.

Metachromatic Leukodystrophy: Inherited disorder of myelin metabolism with progressive loss of white matter in the central and peripheral nervous system.

Pelizaeus-Merzbacher Syndrome: A very rare slowly progressive dysmyelinating disease affecting in a diffuse pattern the cerebrum, cerebellum, brainstem, and spinal cord. Two types are described: X-linked (infantile form) and the autosomal dominant (preadulthood form). Clinical features also include: stridor, muscle spasticity, nystagmus. Often fatal in the first year of life from respiratory complications.

X-Linked Adrenoleukodystrophy (XLA): A disorder characterized by progressive demyelinization of the CNS and peripheral adrenal insufficiency.

Schilder Syndrome: A rare, progressive and lethal disease of the CNS that affects mostly children and is characterized by adrenal atrophy and diffuse central demyelination. Presents with progressive dementia, spasticity, cortical blindness, deafness, hemiplegia, quadriplegia, ataxia, pyramidal signs, retrobulbar neuritis, and pseudobulbar palsy. Seizures. Onset in late childhood. Most patients die within few months after onset.

Chondrodysplasia Punctata: Chondrodysplasia punctata refers to a heterogeneous group of disorders, which have ichthyosis and bony abnormalities probably because of abnormalities of steroidal biosynthesis in common. The international nomenclature and classification of osteochondrodysplasias classified the subtypes of chondrodysplasia punctata as (1) Rhizomelic type, (2) Zellweger Syndrome, (3) Conradi-Hünermann type, (4) X-linked recessive type, (5) Brachytelencephalangic type, (6) Tibial-metacarpal type, (7) Vitamin K-dependent coagulation defect, (8) Other and acquired genetic disorders including warfarin embryopathy. Specific features of the most common individual types of chondrodysplasia punctata are given below.

Benign Congenital Hypotonia: A nonprogressive neuromuscular disorder that occurs at birth. It is characterized by muscle weakness or “floppiness.” It is a disorder of unknown cause and most often considered as a symptom of other neuromuscular diseases.

Nemaline Rod Myopathy: A hereditary muscular disease characterized by hypotonia. The presence of “nemaline rods” within the muscle fibers (very fine threads) is characteristic of this disease.

Infantile Muscular Atrophy: A severe and usually progressive neuromuscular disorder in infants. This condition is characterized by a generalized hypotonia in the trunk and extremities. It is the result of degenerative changes in the central horn cells of the spinal cord. It is often referred to as “amyotonia congenital syndrome.”