Pediatrics

Zellweger Spectrum Disorder

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Zellweger Spectrum Disorder? What are the typical findings for this disease?

The peroxisome biogenesis disorders (PBD) include two phenotype groups:

1. Zellweger Spectrum Disorder (ZSD)

a. Zellweger syndrome (ZS) = severe

b. Neonatal adrenoleukodystrophy (NALD) = intermediate

c. Infantile Refsum disease (IRD) = milder

2. Rhizomelic Chondrodysplasia Punctata type 1 (RCDP1)

Zellweger Spectrum Disorder

For ZSD, the manifestations depend on disease severity and patient age. In general, the diagnosis of ZSD should be considered when there is hypotonia, developmental delay, and sensory deficits (hearing and vision). Death in early infancy is the rule for ZS. Children with NALD may live to school age. Adult survival is more likely in IRD.

ZS. This is a classic malformation syndrome [Zellweger CerebroHepatoRenal syndrome]. Patients present as newborns with severe hypotonia, seizures, and characteristic craniofacial dysmorphism with high forehead, large anterior fontanel, hypertelorism, epicanthic folds, high arched palate and micrognathia (Figure 1).

Figure 1.

Characteristic craniofacial dysmorphisms of Zellweger syndrome.

Brain MRI shows microgyria, pachygyria, and heterotopia consequent to neuronal migration defects. Visual defects include cataracts, congenital glaucoma, optic atrophy and pigmentary retinopathy.

Sensorineural deafness is present. Liver involvement includes hepatomegaly, elevated transaminases, cholestasis, and coagulopathy. Renal cysts are apparent on pathology, but not usually clinically significant.

NALD and IRD. Patients present after the newborn period with more varied symptomatology. Hypotonia, failure to thrive, seizures, sensory deficits, and history of cholestasis are usually present. The characteristic Zellweger facies is attenuated. Brain MRI shows nonspecific abnormalities or can be normal.

NALD is distinguished by the occurrence of a leukodystrophy in early childhood with active demyelination in the cerebrum, midbrain and cerebellum and consequent psychomotor regression. Leopard spot retinal pigmentation is characteristic of NALD.

In later childhood, the clinical presentation is dominated by psychomotor retardation, hypotonia, visual loss from retinal degeneration and sensorineural hearing loss. Renal calcium oxalate stones and adrenal insufficiency can develop. Leukodystrophy can occur at any age, and be stable or progressive (Figure 2).

Figure 2.

Children with NALD-IRD have less severe growth and developmental delays. They typically have progressive vision and hearing loss, and are at risk for leukodystrophy. Dental enamel defects occur, shown in the child in the upper right. Although the classic Zellweger facies is not present, there are some facial features reminiscent of this. Note the hypertelorism in the child in the upper left, and the tall forehead in several of the chlidren.

Atypical presentations with preservation of intellect. IRD patients with sensory deficits, but preservation of intellect are known. A novel, emerging group of ZSD patients present with cerebellar ataxia, with or without peripheral neuropathy, and relative preservation of intellect. Age of onset is in early childhood. Sensory deficits are not predominant features, although some have had cataracts. Brain MRI may show cerebellar atrophy (Table I).

Table 1.

Clinical features of ZSD by age of onset

Rhizomelic chondrodysplasia punctata

RCDP presents in the neonatal period with a characteristic skeletal dysplasia. On exam, there is bilateral shortening of the proximal long bones (humerus > femur) and a typical facial dysmorphism with frontal bossing, depressed nasal bridge, small nose and hypoplastic midface (Figure 3).

Figure 3.

Children with RCDP have a characteristic dysmorphic facies, congenital cataracts, rhizomelia, and profound growth and developmental delays. The underlying skeletal dysplasia reduces mobility. These children range in age from 3 months to 6 years.

Skeletal x-rays show vertebral coronal clefts and generalized epiphyseal calcific stippling, called chondrodysplasia punctata (CDP). Bilateral cataracts are present at birth or develop soon thereafter. Seizures, profound psychomotor delays and growth failure ensue. Brain MRI shows nonspecific abnormalities. Some patients have cleft palate, congenital heart disease or renal malformations. The occurrence of congenital heart disease in RCDP patients is as high as 50%.

Lifespan is broad, with some children dying in the first year and others surviving into adulthood.

Milder forms of RCDP show variable growth and developmental delays; however, all have had cataracts and epiphyseal dysplasia.

What other disease/condition shares some of these symptoms?

See Table II (PBD differential diagnosis).

Table 2.

PBD differential diagnosis

What caused this disease to develop at this time?

These disorders are autosomal recessive and panethnic.

The estimated incidence of ZSD is 1/50,000 and RCDP, 1/100,000 births.

ZSD is caused by mutations in any one of 13 PEX genes [PEX1, 2, 3, 5, 6, 9, 10, 11, 12, 13, 16, 19, 26], and RCDP1 is caused by mutations in only one gene, PEX7. The proteins encoded by these genes are required for the formation of new peroxisome membranes and import of matrix enzymes, the whole process being termed peroxisome assembly, or biogenesis. At the cellular level, defects causing ZSD lead to decreased numbers of enlarged peroxisomes that show reduced import of matrix enzymes. These structures are termed peroxisome ‘ghosts’. In contrast, peroxisome numbers are normal in RCDP1 and there is deficiency of only a subset of matrix enzymes.

Normally, there are several hundred peroxisomes per cell, containing matrix enzymes required for multiple metabolic pathways, including the catabolism and synthesis of important cellular lipids. In ZSD, consequent to the lack of functional peroxisomes, metabolites such as VLCFA, phytanic, pristanic and pipecolic acids accumulate, while others, such as ether phospholipids and docosahexaenoic acid are deficient. It is not clear which pathway contributes most to pathophysiology, but defects in β-oxidation are suspect. In RCDP1, the PEX7 defect impairs ether phospholipid biosynthesis, leading to reduced plasmalogen levels, which are known to be the major pathologic factor. In RCDP1, phytanic acid α-oxidation is also impaired but β-oxidation is normal.

Peroxisome enzyme functions

See Table III (Peroxisome enzyme functions).

Table 3.

Peroxisome enzyme functions

Genotype/phenotype correlations

PEX alleles associated with milder or variant ZSD and RCDP1 phenotypes are usually the outcome of missense or ‘leaky’ splice site mutations, allowing the production of residual PEX proteins that have partial function. At the cellular level, more functional peroxisomes are observed. Measurement of peroxisome metabolites in blood also shows levels that correlate to phenotype. See Table IV (PBD phenotype and relation to peroxisome metabolite levels in blood).

Table 4.

PBD phenotype and relation to peroxisome metabolite levels in blood

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

See Table V (Ancillary laboratory studies helpful when there is suspicion of PBD) and Table VI (Diagnostic laboratory studies for PBD).

Table 5.

Ancillary laboratory studies helpful when there is suspicion of PBD

Table 6.

Diagnostic laboratory studies for PBD

Would imaging studies be helpful? If so, which ones?

Radiology/ultrasound studies:

ZSD

Epiphyseal calcific stippling, or chondrodysplasia punctata (CDP) in knees and hips

Swallow dysfunction and reflux

Renal and cardiac malformations: Renal cortical cysts, horseshoe kidney, cardiac septal defects

RCDP

Generalized CDP and vertebral coronal clefts (less apparent after 1-2 years of age), rhizomelic limb shortening, metaphyseal flaring, irregular, broad or cupped metaphyses, vertebral disc calcification, dislocated hips, small thorax. Long-term survivors have osteopenia.

Swallow dysfunction and reflux

Renal and cardiac malformations: ureteropelvic junction obstruction, cardiac septal defects, tetralogy of Fallot

Neuroimaging:

ZSD

Neuronal migration disorders, dysmyelination, agenesis of the corpus callosum, subependymal germinolytic cysts, ventricular dilation, cerebellar vermis hypoplasia, leukodystrophy.

The finding of medial pachygyria and lateral (perisylvian) microgyria is a distinguishing feature of ZS.

RCDP

Diffuse cerebral/cerebellar atrophy, ventricular enlargement, delayed myelination, dysmyelination, decreased choline/creatine ratio and increased levels of mobile lipids on MRS.

Compression of the cervical spinal cord can occur and may warrant intervention.

Confirming the diagnosis

Suspicion of PBD based on history, examination, imaging studies, ancillary laboratory studies

ZSD:

Measure plasma very long chain fatty acids (VLCFA), phytanic acid and RBC plasmalogens

a) Normal: Unlikely to have ZSD, consider other diagnoses

b) Elevated VLCFA: Consistent with a peroxisomal β-oxidation defect. The diagnosis of ZSD requires abnormalities in more than one peroxisome pathway. Typically, erythrocyte plasmalogens (decreased), plasma phytanic (increased) and pristanic acid (increased) are measured. Additional metabolites that can be evaluated are plasma or urine pipecolic acid and bile acids. (Note that the phytanic acid levels in infancy are normal because this is a dietary compound that is absent from infant formulas and breast milk).

i) Abnormal metabolites are confirmed by enzymatic assays on cultured fibroblasts to measure VLCFA levels, plasmalogen biosynthesis, phytanic acid oxidation and catalase solubility

ii) PEX gene sequencing

c) Note that 10%-15% of patients with a clinical diagnosis of ZSD will have a single peroxisomal enzyme defect in β--oxidation, either D-bifunctional protein or Acyl-CoA oxidase deficiency, and NOT a PEX gene defect. This is distinguished in the metabolite profile and confirmed on cultured fibroblasts. It does not change the diagnostic evaluation, prognosis or management. D-bifunctional protein or Acyl-CoA oxidase genes can be sequenced.

Comment. Nearly all patients with ZSD have elevations of VLCFA. RBC plasmalogens can be normal in IRD. Phytanic acid levels are a function of age and diet. Nevertheless, it is useful to measure all three metabolites at once to get some idea of the effect on different peroxisomal functions. Atypical cases are known with normal VLCFAs. With clinical suspicion, measurement of additional peroxisome functions is warranted. Studies on skin fibroblasts can be informative in difficult cases, as well in PEX gene sequencing.

RCDP1:

Measure RBC plasmalogens and phytanic acid

a) Normal plasmalogens: Unlikely to have RCDP

b) Reduced plasmalogens: Likely to have RCDP

i) Elevated phytanic acid

(a) RCDP1. Since phytanic acid is a dietary compound not present in infant formulas or breast milk, this test may be normal in infancy.

(b) Normal phytanic acid. Establish a fibroblast culture to assay plasmalogen biosynthesis and phytanic acid oxidation:

In 90% of cases, there is reduced plasmalogen biosynthesis and phytanic acid oxidation consistent with RCDP1. PEX7 gene sequencing can be done.

In 10% of cases, there is reduced plasmalogen biosynthesis and normal phytanic acid oxidation consistent with single enzyme defects in plasmalogen synthesis.

a. GNPAT enzyme deficiency diagnoses RCDP2. GNPAT gene sequencing can be done.

b. AGPS enzyme deficiency diagnoses RCDP3. AGPS gene sequencing can be done.

If you are able to confirm that the patient has a peroxisome biogenesis disorder (PBD), what treatment should be initiated?

There is no curative treatment for PBD. Management is multidisciplinary and based on surveillance of feeding, hearing, vision, liver function, neurologic, orthopedic and developmental assessment. Care is palliative for patients with severe disease.

Genetic counseling and family support provide crucial assistance to parents in their decision-making process. The geneticist, neurologist, and nutritionist should be involved early in the management of patients with PBD.

Symptomatic treatment:

ZSD (NALD, IRD): hearing aids and cochlear implants, cataract removal, eye glasses, focused educational programs, physiotherapy, gastrostomy if indicated to ensure appropriate caloric intake, elemental formulas and supplementation of fat soluble vitamins (especially vitamin K) in children with malabsorption, antiepileptics for seizures.

RCDP: cataract removal, eye glasses, physiotherapy, orthotics, gastrostomy if indicated to ensure appropriate caloric intake, antiepileptics for seizures, lotions or hydrocortisone creams for ichthyosis. Due to severe joint limitations, assistive toys/devices can help these children interact. Rigorous attention to pulmonary status is important to prevent respiratory infections.

Therapies targeted to metabolic defects (efficacy studies have not been done):

ZSD (NALD, IRD)

1) To prevent phytanic acid accumulation: restrict foods rich in phytanic acid such as cow’s milk and its by-products. Note that all infant formulas are already low in phytanic acid.

2) Supplement end products that are not made:

Primary bile acids, cholic and chenodeoxycholic acid (100 mg/day).

Docosahexaenoic acid (DHA-100-500 mg/day).

RCDP

1) For RCDP1: To prevent phytanic acid accumulation: restrict foods rich in phytanic acid such as cow’s milk and its by-products. Note that all infant formulas are already low in phytanic acid.

2) For all types of RCDP: Supplementation with DHA if levels are low. (There is evidence that plasmalogens preferentially store DHA, and thus DHA levels can be low in RCDP.)

Possible future therapeutic options for PBD may include:

Pharmacological enhancement of peroxisomal β-oxidation

Oral plasmalogen precursor supplementation

Pharmacological induction of peroxisome numbers

Pharmacological enhancement of activity of a defective PEX protein using chaperone therapies

What are the adverse effects associated with each treatment option?

What are the possible outcomes of PBDs?

ZSD:

Children with ZS usually die in the first year of life, having made little developmental progress. Most children with NALD/IRD achieve delayed milestones and may walk independently. Expressive language is less common, but some children have near normal language for age. Milder phenotypes with preserved intellect and survival into adulthood are known, but are atypical.

Most individuals experience progressive visual and hearing loss.

Feeding difficulties related to swallow and reflux can necessitate gastrostomy tube placement.

A leukodystrophy can develop at any time, and can herald developmental regression and onset of spasticity. This may be stabilize, or progress and be fatal.

RCDP:

Expectations for developmental achievements are exceedingly limited, and growth is poor secondary to the skeletal involvement.

Most infants require gastrostomy tube placement related to difficulties in swallowing and reflux. Gastrostomy tube feeding does not improve growth. Expected weight gains are: ~1 kg in the first 6 months (40 g/week), ½ kg in the second 6 months (20 g/week) and ½ kg/year (40 g/month).

Long-term survivors may have osteopenia with non-traumatic fractures.

It has been estimated if a child reaches the age of 1 year, there is a 67% probability of survival to age 3 years and a nearly 50% probability to survive to school age.

Many patients experience serious respiratory difficulties. The respiratory problems appear to be the most important life-limiting factor in RCDP.

What causes this disease and how frequent is it?

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How do these pathogens/genes/exposures cause the disease?

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Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of PBDs?

ZSD: Seizures, coagulopathy, aspiration

NALD/IRD: Seizures, aspiration, leukodystrophy, progressive visual and hearing loss, adrenal dysfunction, calcium oxalate renal stones, tooth enamel defects

RCDP: Seizures, aspiration, recurrent pulmonary illnesses, cervical stenosis, cataracts. Painful joints in the neonate usually improve.

Are additional laboratory studies available; even some that are not widely available?

Fibroblast complementation studies to determine the defective PEX gene are no longer part of the clinical work-up in most cases.

Direct sequencing of selected PEX genes are likely to be replaced by exome sequencing in the near future

How can Zellweger spectrum disorder be prevented?

Genetic counseling and prenatal diagnosis:

PBD are heterogeneous, autosomal recessive disorders.

Carriers (heterozygotes with one mutant and one normal allele) are healthy.

The parents of an affected child (the proband) are obligate carriers. In rare instances (<1%), one parent is not a carrier and the disorder in the child occurs secondary to uniparental disomy, or

de novo mutation in the sperm or egg cell. This can only be detected by evaluating the parents for the mutations identified in the child and significantly changes the recurrence risks.

Each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being a non-carrier. If a sibling is not affected, his/her chances of being a carrier are 2/3.

Each sibling of the proband’s parents is at a 50% risk of being a carrier.

Mildly affected ZSD individuals have had children.

Prenatal diagnosis is available based on biochemical determination of peroxisome functions in cultured fibroblasts or PEX gene sequencing. Preimplantation genetic diagnosis could be offered if the PEX gene mutations are known, and has been successful.

What is the evidence?

Treatment in PBD is mainly supportive. Dietary restrictions and supplementations targeted to the metabolic defects are instituted to correct abnormalities in phytanic acid accumulation, plasmlaogen deficiency, DHA deficiency and primary bile acid deficiency. Their efficacy is not known as proper clinical trials have not been performed.

Braverman, NE, Moser, AB, Steinberg, SJ. "Rhizomelic chondrodysplasia punctata type 1". GeneReviews at GeneTests: Medical Genetics Information Resource (database online). University of Washington. May 2014 . pp. 1997-2011. http://www.ncbi.nlm.nih.gov/books/NBK1270/.

(Review of phenotype, genotype, diagnosis and management for clinicians.)

Steinberg, SJ, Raymond, GV, Braverman, NE, Moser, AB. "Peroxisome biogenesis disorders, Zellweger syndrome spectrum". Gene Reviews at GeneTests: Medical Genetics Information Resource (database online). University of Washington. pp. 1997-2011. http://www.ncbi.nlm.nih.gov/books/NBK1448/.

(Review of phenotype, genotype, diagnosis and management for clinicians.)

Wanders, RJA, Sarafoglu, K, Hoffman, GF, Roth, KS. "Inborn errors of peroxisome biogenesis and function(chapter 24)". Pediatric endocrinology and inborn errors of metabolism. McGraw Hill. 2009. pp. 323-37.

(Review of PBD for clinicians with additional charts and tables.)

Steinberg, SJ, Dodt, G, Raymond, GV, Braverman, NE. "Peroxisome biogenesis disorders". Biochim Biophys Acta. vol. 1763. 2006. pp. 1733-48.

(Review of phenotype, genotype and diagnosis for clinicians and scientists.)

Wanders, RJ, Waterham, HR. "Biochemistry of mammalian peroxisomes revisited". Annu Rev Biochem. vol. 75. 2006. pp. 295-332.

(A comprehensive review of the peroxisome biochemistry.)

Ongoing controversies regarding etiology, diagnosis, treatment

N/A

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