Zellweger Syndrome: A Downs Syndrome Mimic

The peroxisomal diseases are genetically determined disorders caused either by the failure to form or maintain the peroxisome or by a defect in the function of a single protein that is normally located in this organelle. It is a heterogeneous group of autosomal recessive disorders characterized by a defect in peroxisome formation and are caused by mutations in one of 13 PEX genes. The defect in peroxisome formation or impaired metabolic pathways result in metabolic abnormalities. Typically in Zellweger spectrum disorders (ZSD) patients accumulate very long chain fatty acids (VLCFAs), phytanic and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes.These disorders present with a wider range of phenotype than has been recognized in the past and few of them may phenotypically resemble Downs Syndrome. Keyword: Peroxisomal diseases, PEX genes, Zellweger spectrum disorders, Very long chain fatty acids, Plasmalogens, Downs Syndrome ...................................................................................................................................................


Introduction
Zellweger syndrome (ZS) as a cerebro-hepato-renal syndrome was first described in 1964 by Bowen et al [1]. The clinical presentations have clinical overlap in terms of morphological features. Some of the phenotype mimic Downs syndrome [1,2]. Despite of being a cerebro-hepato-renal syndrome in literature, we present a case with predominant neurological involvement without any hepatic or renal manifestations at presentation. The diagnosis was suspected only on basis of clinical phenotype resembling downs syndrome with a normal karyotype.

Case Summary
We report a case of 3-month-old girl presented with fever and vomiting for 3 days with lethargy, refusal to feeds for a day prior admission. There was no significant past history and family history. Perinatal period was uneventful however antenatal ultrasound was suggestive of polyhydramnios.The child presented in status epilepticus, jerky respiration and apneic spells.
The hand of the patient had simian crease with clinodactyly, absent bilateral proximal interphalangeal flexure lines on index finger, middle finger and no flexure lines on bilateral little finger. No neurocutaneous markers were present. Spine was normal (Fig 3 and 4) On Systemic examination child had marked hypotonia, hyper reflexia, firm hepatomegaly. Fundus examination was normal. Child required ventilatory support and was stabilised with treatment with antibiotics for 3 days, inotropic support for first 24 hours of admission. Status epilepticus was controlled by Fosphenytoin, Phenobarbitone, Levetiracetam. After initial stabilisation she was further evaluated for dysmorphism mimicking Downs syndrome. Karyotype (46XX) and Thyroid function tests done postnatally were normal.  Child was planned for a work up keeping Zell wegers Spectrum disorders owing to a phenotype suggestive of Downs syndrome but a normal karyotype. Hence a Very long chain fatty acid assay was done which reported an elevated C26 and C26/C22. RBC plasmalogen/Fatty acid ratio reported normal C16:0 DMA/C16:0 fatty acid and low C18:0 DMA/C1:0 fatty acid ratios. The report was hence consistent with Zell wegers Syndrome.

Pediatric Review: International Journal of Pediatric Research
Available online at: www.medresearch.in 78|P a g e Child was discharged on a phytanic free diet, antiepileptics, docosahexaenoic acid (DHA) and multivitamin supplementation. Child was followed up on monthly intervals however patient did not follow up after 6 months of age. The plan for further confirmation of diagnosis in cultured skin fibroblast, DNA sequencing of PEX and related peroxisomal single enzyme defects genes for mutations as mentioned in literature were not feasible due to financial constraints [1]. Patients that present in childhood or adolescence usually have a better prognosis, but can develop progressive liver disease or leukodystrophy and gradually deteriorate. Despite early presentation with ZS our patient did not have any liver involvement. Progressive liver disease or leukodystrophy are poor prognostic indicators.

Discussion
The remaining milder individuals can reach adult hood without progression or with long periods of stabilization. When progression occurs, it is mainly related to peripheral neuropathy and pyramidal signs, while cognition remains stable.
Most patients with ZS succumb in first year of life. The incidence is variable worldwide with highest in Quebec (1 in 12) and lowest inJapan(1 in 5,00,000) [2]. We could narrow down our differentials by karyotype and a normal thyroid function test. The final diagnosis was established based on Very long chain fatty acid and RBC plasmalogen/Fatty acid ratio done as our patient had a Downs phenotype.
MRI was done to look for CNS migration defects. Very long chain fatty acid and RBC plasmalogen/Fatty acid ratio were consistent with Zell wegers Spectrum disorder.
Like any other syndromes, Zell wegers spectrum disorders too have a variation in phenotypes from case to case, we enlist few features in the Table 1 based on earlier reported case reports [3][4][5][6].
The treatment modalities at presentdovetail clofibrate, glycerol and the oral administration of DHA in an attempt to achieve postnatal correction of the biochemical abnormalities [4].
However, in view of the multiplicity and severity of the defects only supportive care is recommended. The supportive care would be supplementing cortisone for adrenal insufficiency, Vitamin K supplementation for Coagulopathy, use of antiepileptic drugs for seizure control, oral citrate treatment for hyperoxaluria, Supplementation of fat soluble vitamins (A,D,E), appropriate visual and hearing aids for respective impairment.
Surgical interventions like cataract removal or gastrostomy may be needed as and when warranted.    Table 2 illustrates the recommend able and avoidable food items in ZS [7,8,9].

Table-2: Food items recommended and avoidable in ZS.
No phytanic-Safely recommended foods High Phytanic-Not recommended foods Fruits, Cereals and vegetables Fish sunflower and safflower oils All milk products poultry or pig meats beef, rabbit meats, sheep and goat products Breast milk (especially of fish consuming mothers for DHA) Most patients succumb in infancy. Antenatal diagnosis is hence needed. There is are port on the successful application of Preim plantation genetic diagnosis (PGD) in a family affected with Zellweger syndrome (ZS) caused by a mutation in PEX26 gene. This was the first successful report of PGD for ZS, with the subsequent delivery of a homozygous normal baby after delivering 4 children with ZS and therapeutic abortion may hence not be needed in future [10].