Zellweger Syndrome

Zellweger syndrome (ZWS), also called cerebrohepatorenal syndrome, is a rare congenital peroxisome biosynthesis disorder and is considered an inborn error of metabolism. Zellweger syndrome is the most severe form of a spectrum of conditions called Zellweger spectrum disorder (ZSD), and is characterized by the reduction or absence of functional peroxisomes. Symptoms are present from the time of birth and include hypotonia, poor feeding, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and certain distinctive physical features, notably facial characteristics and skeletal malformations. There is no cure for ZWS. The average survival rate is less than 1 year.

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Epidemiology and Genetics

Epidemiology

  • Incidence: 1:50,000–100,000
  • Most common peroxisome biosynthesis disorder is seen in infancy.
  • Most infants born with Zellweger syndrome (ZWS) do not live past 6 months.

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

  • Inheritance: autosomal recessive
  • Due to a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in 1 of 13 PEX genes, which encode peroxins → proteins required for the normal assembly of peroxisomes:
    • Peroxisomes are membrane-bound organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles present in all cells, except mature erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes:
      • Contain enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes necessary for multiple catabolic and anabolic metabolic functions 
      • Catalyze beta-oxidation of very long chain fatty acids (VLCFAs)
      • Catalyze oxidation of phytanic, pipecolic, pristanic, and other dicarboxylic acids
      • Involved in synthesis of bile acids and plasmalogen
    • PEX gene mutations result in a loss of peroxisomal function → preventing catabolism of VLCFAs → ↑ accumulation of VLCFAs in membranes of neuronal cells → abnormal function, atrophy, and death of cells → impaired neuronal migration and differentiation → abnormal brain development → neurologic dysfunction and injury to variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables extents 
  • Most commonly a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the PEX1 gene

Clinical Presentation

Clinical manifestations of ZWS are present at birth.

Craniofacial dysmorphism

  • Separated cranial sutures
  • Large anterior fontanelle
  • High forehead
  • Flattened face
  • Low and broad nasal bridge
  • Upslanting palpebral fissures 
  • Epicanthal folds ( skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin fold from the upper eyelid to the inner corner of the eye)
  • Protruding tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue
  • Deformed ear lobes
  • High arched palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate
Craniofacial dysmorphic features in patients with zellweger spectrum disorders (zsd)

Craniofacial dysmorphic features in patients with Zellweger spectrum disorder (ZSD)
A 6-month-old girl (A) with typical craniofacial dysmorphia, epicanthal folds, high forehead, broad nasal bridge, hypoplastic supraorbital ridges, and large anterior fontanel (drawn). Images (B) and (C) show a girl with ZSD at the age of 9 months (B) and 14 months (C). Facial dysmorphism in this girl is less pronounced.

Image: “Zellweger spectrum disorders: clinical overview and management approach” by Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. License: CC BY 4.0, edited by Lecturio.

Neurologic abnormalities

  • Severe hypotonia and muscle weakness
  • Epileptic seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
  • Absent reflexes
  • Developmental delay

Ocular abnormalities

  • Vision impairment 
  • Cataracts
  • Pigmentary retinopathy
  • Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma

Hepatic abnormalities

  • Hepatomegaly
  • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
  • Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Coagulopathy
  • Biliary dysgenesis (affects the normal movement of bile)

Renal abnormalities

  • Glomerulocystic kidney disease
  • Renal dysfunction

Associated conditions

  • Chondrodysplasia punctata present in 50%–70% of cases:
    • Encompasses a group of skeletal anomalies characterized by calcific deposits in cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage (calcific stippling), particularly in the patella and long bones
    • Associated with shortened limbs, joint contractures, and spinal abnormalities
  • Feeding difficulties due to profound hypotonia

Diagnosis and Management

Diagnosis

  • History and clinical examination
  • Laboratory studies:
    • Blood:
      • ↑ Plasma VLCFA concentration
      • ↑ Bile acid intermediaries di- and trihydroxycholestanoic acid (DHCA, THCA)
      • ↑ Phytanic, pristanic, and pipecolic acid concentrations
    • Erythrocytes: ↓ plasmalogen concentration
    • Urine:
      • ↑ Bile acids
      • ↑ Pipecolic acid concentration
  • Imaging:
    • Brain magnetic resonance imaging (MRI): may show various abnormalities including neocortical dysplasia, impaired myelination, abnormal cortical gyral patterns, decreased volume of white matter, bilateral ventricular dilatation, and germinolytic cysts 
    • Abdominal ultrasound: shows hepatomegaly and/or renal cysts
  • Assays of peroxisomal-related processes in cultured skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin fibroblasts help confirm the diagnosis.
  • Genetic testing: identifies the specific molecular defect to confirm the diagnosis 
  • In utero diagnosis by chorionic villus sampling may be done if there is a suspicion of the disorder or a family history.

Management

There is no cure and no effective treatment for ZWS. Treatment is supportive at best. 

  • Feeding issues may be treated with a nasogastric tube.
  • Therapeutic and genetic counseling should be offered to the family.

Prognosis

Death typically occurs within 1 year of birth (usually < 6 months), typically due to respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure

Clinical Relevance

Related conditions

Zellweger syndrome is part of a clinical continuum of peroxisome biogenesis disorders known as Zellweger spectrum disorder (ZSD). All of the following conditions also have autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceinheritance, and are diagnosed and managed similar to ZWS: 

  • Neonatal adrenoleukodystrophy (NALD): considered a less-severe form of ZSD than ZWS. Craniofacial dysmorphism is present, but less severe, with mid-face hypoplasia usually the most pronounced. Individuals with NALD also have hepatic dysfunction and may have adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease, but cystic renal disease and chondroplasia punctata are absent. Neurologic dysfunction with progressive leukodystrophy (degeneration of brain white matter) begins in the early years of life. Most children do not survive past 5 years of age. 
  • Infantile Refsum disease (IRD): the clinical presentation is less severe than ZWS and NALD. Facial dysmorphic features are mild or may be absent. Hepatic dysfunction and neurologic features such as hypotonia and vision and hearing impairments occur. Severe developmental delay is noted within the 1st 6 months of life. Gastrointestinal symptoms also occur. Neurologic deterioration is slower and children with IRD may survive into adolescence. 
  • Heimler syndrome: an extremely rare peroxisomal biogenesis disorder that is considered the mildest form of ZSD. Heimler syndrome is characterized by acquired sensorineural hearing loss, retinal dystrophy or pigmentosa, nail abnormalities, and enamel hypoplasia of permanent teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth. The remainder of development and cognition appear to be normal. The lifespan is unaffected. 

Differential diagnosis

The differential diagnosis for ZWS is vast. Clinical features, biochemical testing, imaging, and ultimately genetic testing help to differentiate and provide a diagnosis. The following are disorders that should be considered in any neonate that presents with profound hypotonia:

  • Chromosomal abnormalities:
    • Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down Syndrome (Trisomy 21)
    • Prader-Willi syndrome Prader-Willi syndrome Prader-Willi syndrome (PWS) is a rare autosomal neurodevelopmental genetic disorders mapped to a specific region of chromosome 15 attributed to genomic imprinting. A paternally derived chromosome 15 with this deletion results in 15q11-13 paternal deletion syndrome, or PWS. Prader-Willi Syndrome and Angelman Syndrome 
  • Single enzyme peroxisomal disorders: 
    • Acyl-CoA oxidase deficiency (also known as pseudo-NALD) 
    • D-bifunctional protein deficiency
  • Other metabolic disorders: 
    • Acid maltase deficiency (AMD)
    • Carnitine deficiency
    • Cytochrome C oxidase deficiency
  • Neuromuscular disorders:
    • Spinal muscular atrophy Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a spectrum of autosomal recessive syndromes characterized by progressive proximal muscle weakness and atrophy, possibly due to degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. Spinal Muscular Atrophy (SMA)
    • Congenital muscular dystrophies
    • Congenital myopathies
  • Infections:
    • Cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus (CMV)
    • Rubella virus Rubella Virus Rubella (also known as German measles or three-day measles) is caused by a single-stranded, positive-sense RNA virus of the Togaviridae family and the Rubivirus genus. Rubella only infects humans and spreads prenatally via vertical transmission or postnatally via droplet contact. Rubella Virus
    • Toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis
    • Herpes simplex virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview ( HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2)

References

  1. Wanders, R. J. & Schiffman, R. (2020). Peroxisomal disorders. UpToDate. Retrieved December 14, 2020, from https://www.uptodate.com/contents/peroxisomal-disorders
  2. Klouwer, F.C.C., Berendse, K., Ferdinandusse, S. et al. (2015). Zellweger spectrum disorders: Clinical overview and management approach. Orphanet J Rare Dis. 10(151) https://doi.org/10.1186/s13023-015-0368-9
  3. Steinberg SJ, Raymond G V, Braverman NE, & Moser AB. (2020). Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. Gene Reviews. http://www.ncbi.nlm.nih.gov/books/NBK1448/
  4. Gao, FJ., Hu, FY., Xu, P., et al. (2019). Expanding the clinical and genetic spectrum of Heimler syndrome. Orphanet J Rare Dis. 14, 290. https://doi.org/10.1186/s13023-019-1243-x
  5. Böhm, M., Pronicka, E., et al. (2006). Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency. Pediatric research, 59(1), 21–26. https://doi.org/10.1203/01.pdr.0000190572.68191.13

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