Peroxisomal Disorders Clinical Presentation

Updated: Jul 29, 2020
  • Author: Hoda Z Abdel-Hamid, MD; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA  more...
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Four-group classification by clinical criteria

Peroxisomal disorders also can be classified into 4 groups based on clinical criteria.

Group 1 includes disorders of peroxisome biogenesis (PBD) that share the ZWS phenotype, such as ZWS, a subgroup sharing with ZWS a general loss of all peroxisomal enzymes (ie, NALD, infantile Refsum disease [IRD], hyperpipecolic academia [HPA]); disorders displaying the ZWS phenotype in which peroxisomes are present; those with a deficiency of only 1 enzyme of peroxisomal beta-oxidation (eg, pseudo–NALD, pseudo-ZWS, bifunctional protein insufficiency); and disorders displaying the ZWS phenotype characterized by the loss of several enzymes and a normal amount of peroxisomes. In ZWS-like syndrome, enzymes for peroxisomal beta-oxidation are still unidentified.

Group 2 contains the RCDPs and related bone dysplasias. RCDP types II and III are due to plasmalogen deficiency.

Group 3 includes the X-ALD and phenotypic variants.

Group 4 comprises hyperoxaluria, acatalasemia, Refsum's disease, mevalonate kinase deficiency, glutaryl-CoA oxidase deficiency, and dihydroxy or trihydroxy cholestanoic acidemia (enzyme unknown).

Two-group classification based on organelle structure and deficiencies

Although different classifications have been proposed, the growing consensus supports a classification in which 2 groups of disorders are distinguished: (1) disorders of peroxisomal biogenesis (PBD) in which the organelle is abnormally formed and missing several functions and (2) single-enzyme deficiencies with intact peroxisomal structure.

The second group includes at least 10 disorders in which the defect involves a single peroxisomal protein but the structure of the peroxisome is intact. This category includes ALD (ie, VLCFA synthesis deficiency), AMN, pseudo–neonatal ALD (ie, NALD, or acyl-CoA oxidase deficiency), metabolic kinase deficiency, hyperoxaluria type I (ie, alanine glyoxylate aminotransferase deficiency), bifunctional enzyme deficiency, pseudo-ZWS (ie, peroxisome thiolase deficiency), acatalasemia (ie, catalase deficiency), dihydroxy acetone phosphate (DHAP) acyltransferase (AT) deficiency (ie, DHAP-AT deficiency, or type II rhizomelic chondrodysplasia punctata [RCPD]), alkyl-DHAP synthase deficiency (ie, type III RCDP), glutaric aciduria type III, and classic Refsum disease (ie, phytanoyl-CoA hydroxylase deficiency).

  • PDBs are due to mutation or mutations in the PEX genes that normally encode for peroxin proteins and whose proper expression is required for peroxisome biogenesis. Fourteen distinct PEX genes have been described.

    • Zellweger syndrome

      • ZWS is considered to be the prototype of the PBD group, which includes NALD, IRD, and HPA. Bowen et al first described ZWS in 1964. [4] Passarge and McAdams introduced the name cerebrohepatorenal syndrome.

      • ZWS causes multiple congenital anomalies dominated by a typical craniofacial dysmorphism, including a high forehead, a large anterior fontanelle, hypoplastic supraorbital ridges, broad nasal bridge, micrognathia, deformed ear lobes, and redundant nuchal skin folds.

      • The neurologic picture comprises severe psychomotor retardation, profound hypotonia with depressed deep tendon reflexes (DTRs), neonatal seizures, and impaired hearing. Brain anomalies include cortical dysplasia with pachygyria and neuronal heterotopia; regressive changes related to storage with subsequent cell death may be seen. Dysmyelination rather than demyelination is observed.

      • Ocular findings include congenital cataract, glaucoma and retinal degeneration with an absent electroretinogram (ERG).

      • Other abnormalities are calcific stippling of the epiphyses, small renal cysts, and liver cirrhosis.

      • Patients with ZWS have a decreased number of hepatic peroxisomes, impaired plasmalogen synthesis (especially in RBCs) and increased levels of VLCFA, bile acids, pipecolic, and phytanic acids. These findings suggest the involvement of different peroxisomal pathways.

      • Patients with NALD and IRD have less severe disease and longer survival rates than those of patients with ZWS. Sensorineural hearing loss and pigmentary retinal degeneration is invariably present. Leukodystrophy may develop in the mild phenotypes; however, migration defects are not common, and seizures are usually absent in IRD but not in NALD, which involves exclusive atrophy of the adrenal cortex. Likewise, renal cysts and chondrodysplasia punctata are not typically present. However, short stature and delayed eruption of teeth are noted.

      • HPA is considered to belong to the PBD group; however, isolated HPA is rare and not well understood.

  • Rhizomelic chondrodysplasia punctata 1

    • RCDP type 1 is a heterogenous group of disorders that is clinically distinct from the ZWS.

    • Various forms of inheritance with autosomal or X-linked, dominant, or recessive patterns have been described.

    • Peroxisomal abnormalities are found in only the rhizomelic autosomal recessive variant. Patients with these abnormalities have short stature, with spasticity and contractures, dysmorphic facies, and severe mental retardation. Shortening mainly involves the proximal parts of the limbs. Patients suffer mostly from severe scoliosis and chronic chest infection. Skeletal radiography typically reveals bone dysplasia with epiphyseal stippling. Death occurs in the first decade of life. Plasmalogen deficiency is a consistent feature and highly reliable for diagnosis.

  • Single-enzyme deficiencies with intact peroxisomal structure include disorders of peroxisomal beta-oxidation (POD), disorders of ether-phospholipid biosynthesis, and disorders of fatty acid alpha-oxidation.

    • Disorders of peroxisomal beta-oxidation - X-ALD

      • These disorders, seen only in males, are due to mutations in the ABCD1 gene. [5] This gene encodes for ABC, a transporter molecule involved in the uptake of VLCFA across peroxisomal membranes. This mutation results in the accumulation of VLCFA due to lack of peroxisomal oxidation. Clinical presentations are diverse, ranging from the lethal cerebral childhood form to an isolated Addison-like disease with no neurologic involvement. Phenotypes in the same pedigree are markedly heterogeneous, a phenomenon attributed to the action of a possible modifier gene.

      • Semmler et al have suggested that polymorphisms of genes involved in methionine metabolism modify phenotype in X-ALD, and have found evidence that the Tc2 genotype contributes to X-ALD phenotype generation. [6]

      • Approximately 20% of women who are heterozygous for the ALD locus develop neurologic disability that is milder and later in onset than that observed in affected men. Deficits vary from mild hyperreflexia and vibratory sense impairment to paraparesis causing patients to use a wheelchair. Signs of dementia are rare. The implicated gene is subject to X-inactivation.

      • In the cerebral form of X-ALD, early development is entirely normal, and the first neurologic manifestations most commonly occur at 4-8 years of age. Asymptomatic boys may have a normal full-scale IQ but a low performance IQ. [7] Early manifestations are often mistaken for attention-deficit/hyperactivity disorder. Characteristic neurologic manifestations, such as impaired auditory discrimination, visual disturbances, spatial disorientation, poor coordination, and seizures supervene later in the disease, which may then progress rapidly. Progression leads to a vegetative state in 2 years and death at some point thereafter. Relatively uncommon adolescent and adult cerebral forms can occur. An inflammatory response is seen in the cerebral form.

      • AMN, another variant of X-ALD, causes slowly progressive paraparesis and sphincter disturbances and is often misdiagnosed as multiple sclerosis. Symptoms typically start at 28 ± 9 years. Forms include pure AMN and AMN-cerebral. Patients with pure AMN present with only spinal cord and peripheral nerve involvement and sparing of higher cognitive functions. However, neuropsychological testing may show subtle deficits in psychomotor speed and visual memory. This variant has a better prognosis than that of other forms. AMN-cerebral is used to describe increased impairment of neuropsychological function. Patients have various degrees of brain MRI abnormalities.

      • Progressive cerebellar disorder resembling olivopontocerebellar degeneration is described.

      • The Addison-like phenotype is distinguished from Addison disease by high levels of serum VLCFA.

      • Patients with acyl-CoA oxidase deficiency, or pseudo-NALD, have a ZWS phenotype but no dysmorphic features. Symptoms consist of hypotonia, psychomotor regression, seizures, deafness and retinopathy with hypodensity of the cerebral white matter in addition to adrenocortical insufficiency. However, all peroxisomal metabolites, for the exception of VLCFA, are normal.

      • D-Bifunctional protein deficiency results in a phenotype similar to that of ZWS, with dysmorphic facies and cerebral migrational defects. levels of both VLCFA and bile-acid intermediates are abnormally elevated. However, peroxisomes appear normal on liver biopsy.

      • Peroxisomal thiolase deficiency, or pseudo-ZWS, is believed to be a subgroup of D-bifunctional protein deficiency.

      • Peroxisomal 2-methylacyl-CoA racemase deficiency (AMACR) is characterized by a defect in beta-oxidation of branched-chain fatty acids. Clinical manifestations consist of adult-onset sensory-motor neuropathy, a symptom also reported in Refsum disease and in the ALD variant. However, phytanic acid and VLCFA levels are normal, though levels of 2-methyl branched-chain fatty acid, pristanic acid, and DHCA and/or THCA are abnormally elevated. Symptoms may vary, and patients may have isolated liver disease without neurologic involvement.

    • Disorders of ether-phospholipid biosynthesis

      • In most patients with RCDP type I, the primary defect involves the PEX-7 gene, which encodes for the peroxisomal targeting sequence (PTS-2) receptor. This receptor helps to target cytosolic proteins to the peroxisome. As a result, multiple peroxisomal enzymes that depend on PTS-2 signaling are affected (eg, peroxisomal thiolase, alkyl DHAP synthase, phytanoyl-CoA hydroxylase, DHAP-AT).

      • RCDP types II and III are characterized by variable severity of clinical manifestations and by disproportionately short stature that primarily affects the proximal parts of the extremities, a typical facial appearance, congenital contractures, cataracts, and mental retardation similar to that of RCDP type I. However, bone stippling is not present. In RCDP types II and III, the PEX-7 protein is normal, and a mutation occurs in the structural gene encoding for their specific enzymes, PHAP-AT and alkyl DHAP synthase, respectively. Plasmalogen is deficient but, unlike RCDP type I, phytanic acid and other peroxisomal metabolites are normal.

      • Mevalonate kinase is implicated in the biosynthesis of isoprenoids. Its deficiency leads to elevated levels of mevalonic acid in the urine. Clinical manifestations include developmental delay, cataracts, hepatosplenomegaly, and lymphadenopathy with early death. Similar symptoms have been observed in patients with hypergammaglobulinemia type D and periodic fever syndrome in addition to skin rash and arthralgias.

      • Acatalasemia is a rare disease variably associated with catalase deficiency and ulcerating oral lesions. It has been described in Japan and in Switzerland.

      • Mulibrey nanism, also known as muscle-liver-brain-eye syndrome, has been described in Finnish people and consists of muscle weakness, constrictive pericarditis, hepatomegaly, and J -shaped sella turcica with enlarged cerebral ventricles. Yellowish dots are noted on funduscopic examination. Patients have severe growth retardation but normal psychomotor development. Plasma VLCFA and liver peroxisomes are normal. The protein involved is strongly suspected but not yet confirmed to be a peroxisomal factor.

      • Patients with hyperoxaluria type I due to deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. Calcium oxalate urolithiasis and nephrocalcinosis is present that leads to progressive renal failure at various ages. In addition, they may develop myocarditis, neuropathy, osteosclerosis, and retinopathy as a result of oxalate deposits in various organs. Urine excretion of glyoxylic and glycolic acid is increased. The enzyme is present only in the liver, and liver biopsy is usually needed for diagnosis.

    • Disorders of fatty acid alpha-oxidation: Refsum disease is the only known type in this group. It is characterized by retinitis pigmentosa, sensory-motor polyneuropathy, cerebellar ataxia, and elevated cerebrospinal fluid protein levels without pleocytosis. Other features include sensory-neural hearing loss, anosmia, ichthyosis, skeletal malformation and cardiac abnormalities. Accumulation of phytanic acid in brain, blood, and other tissues is toxic.