Zellweger Syndrome
| Classification according to ICD-10 | |
|---|---|
| Q87.8 | Other specified congenital malformation syndromes, not elsewhere classified
Zellweger Syndrome |
| ICD-10 online (WHO version 2019) | |
The Zellweger syndrome , also known under the synonym cerebral - hepatic - renal syndrome or cerebro-hepato-renal syndrome , is a very rare, genetically caused, autosomal recessive hereditary peroxisomal metabolic disorder based on a congenital gene mutation . It is fatal.
The disease was first described in pairs of twins by the US doctor of Swiss descent Hans Ulrich Zellweger in 1964 .
Epidemiology
Zellweger syndrome is a rare hereditary disease and can be diagnosed in an estimated 1 in 100,000 newborns . Girls and boys are equally affected.
Since 1964, over 100 cases have been documented that occurred both sporadically and in a sibling .
root cause
The syndrome is primarily characterized by the lack of peroxisomes or a disruption of peroxisomal biogenesis , which is associated with a loss of the corresponding liver , kidney and other organ functions. Furthermore, there is a loss of activity of several peroxisomal enzymes , which affects various metabolic functions .
The pseudo - Zellweger syndrome is distinguished from the real Zellweger syndrome . In this case there is a loss of activity of the acyl-CoA oxidase, a peroxisomal enzyme .
Zellweger syndrome is due to mutations in the genes that are necessary for the development of peroxisomes. These include the serine-lysine-leucine receptor Pex5 and, more often, the gene for the ATPase Pex1.
If there are mutations in PEX1 or PEX5 or other genes for the formation of peroxisomes, the enzyme that is necessary for the cleavage of hydrogen peroxide - a cell poison - the catalase, is no longer smuggled into the peroxisome.
In addition to the catalase reaction, various other biochemical reactions take place in peroxisomes , which have to do with the breakdown and modification of fatty acids. So z. B. Fatty acids that have a chain length of over 22 carbon atoms are only broken down into peroxisomes. Bile acids are also completed in peroxisomes. However, what the essential role of peroxisomes is, the failure of which causes the symptoms in Zellweger syndrome, has not yet been clarified.
Symptoms
Children with Zellweger syndrome are often born prematurely before the calculated due date . Newborns have a combination of peculiarities, although not all characteristics are equally pronounced in all children or in all children. The most common symptoms include:
- Special features of the head and face :
- vertical overdevelopment of the head ( scaphocephalus / long skull )
- poorly developed (hypoplastic) root of the nose
- comparatively short philtrum (hollow between nose and upper lip )
- comparatively flat and rectangular looking face
- high, bulging forehead
- ears set comparatively low on the head
- in newborn children, a comparatively large, not yet ossified area on the skullcap ( fontanel )
- Relocation of the lower jaw and the row of teeth due to a growth disorder ( mandibular retrognathia )
- Soft palate cleft
- movements of the facial surface that are noticeably less visible (reduced facial expressions )
- Special features of the eyes :
- comparatively large eye relief ( hypertelorism )
- flat edges of the bony eye socket ( orbit )
- Corneal opacity
- Lens opacity
- Degeneration of the optic nerve , which leads to loss of visual acuity , visual field defects and extensive blindness ( optic atrophy )
- Brushfield spots (mottling of the iris )
- Epicanthus medialis (small folds of skin on the inner corners of the eyes)
- inclined lid axes
- Peculiarities of the brain
- cerebral cysts (cysts in the brain , subependymal pseudocysts)
- decreased expression of convolutions ( microgyria ) or Windungslosigkeit ( agyria )
- Enlargement of the lateral ventricles in the brain
- Peculiarities of internal organs
- Underdevelopment of the lungs ( pulmonary hypoplasia )
- Special features of the biliary tract
- Special features of the kidneys ( multicystic kidney dysplasia )
- Special features of the liver ( liver failure , severe liver enlargement / hepatomegaly , siderosis / iron storage disorder)
- Special features of the spleen ( siderosis / iron storage disorder)
- Heart defects , especially ventricular septal defects
- Thymic dysplasia
- other special features
- severe cognitive disability
- severe psychomotor developmental delay
- Malformation of the external genital organs in girls
- Disruption of the formation of bone tissue ( ossification )
- shrill-sounding crying
- pronounced reduction in muscle tension ( muscle hypotonia ) with reduced joint mobility
- Reduced reflexes ( hyporeflexia ) or lack of reflexes ( areflexia )
- epilepsy
- Difficulty breathing ( shortness of breath up to life-threatening respiratory failure )
- Short stature (below average growth in length)
- Four-finger furrow
- big, broad thumb
- slight bending of the little fingers and / or the ring fingers in the direction of the next finger on the right ( camptodactyly )
- Special features of the epiphyses (the shaft ends of long tubular bones), especially localized calcifications on the corresponding areas of the knee and hip joints
- due to a lack of propanoyl-CoA acyltransferase, decreased bile salts and accumulations of pristanic acid
diagnosis
Particularly the features of the face, hypotonia, and cysts in the brain and kidneys may indicate Zellweger syndrome in a baby .
A diagnosis can be made via the detection of changes in the fatty acids in the serum (concentration of "excessively long-chain" fatty acids) and plasmalogens . Elevated pipecolic acid and phytanic acid gives another clue. The absence of peroxisomes can be demonstrated in a fibroblast and hepatocyte culture . The diagnosis should be confirmed by identifying the genetic change (mutation).
As part of prenatal diagnostics , i.e. prenatal diagnostics, Zellweger's syndrome can be detected in the examination of the cells of the unborn child following a chorionic villus sampling or amniocentesis based on an above-average content of long-chain fatty acids , reduced plasmalogen concentration and low activity of acyl-CoA: DHAP transferase be diagnosed. No peroxisomes can be seen on appropriate microscopic examinations.
The differential diagnoses pseudo-Zellweger syndrome , 3-oxoacyl-CoA-thiolase deficiency , hyperpipecolacidemia , chondrodystrophia punctata , Refsum syndrome , Smith-Lemli-Opitz syndrome and other peroxisomopathies, and possibly the extremely rare adrenomyodystrophy, should be considered before the Zellweger syndrome is finally diagnosed.
The neonatal Refsum syndrome (IRD) is summarized with the neonatal adrenoleukodystrophy (NALD) and the Zellweger syndrome as peroxisome biogenesis defect (peroxisome biogenesis defect-Zellweger syndrome spectrum).
In principle, it is possible that the syndrome is not recognized as such, but is assigned to one of the possible differential diagnoses, in particular the pseudo-Zellweger syndrome or hyperpipecolacidemia, since a clear separation is not always possible.
therapy
So far, no causally curative treatment or therapy options are known. The Zellweger syndrome is lethal , which means that children with this peculiarity are not viable in the long term. They usually die in the first few months after their birth.
literature
- R. Witkowski, O. Prokop, E. Ullrich, G. Thiel: Lexicon of Syndromes and Malformations 7th edition. Springer, Berlin 2003, ISBN 3-540-44305-3 , pp. 225-226.
- P. Bowen, CSN Lee, HU Zellweger, R. Lindenburg: A familial syndrome of multiple congenital defects. In: Bulletin of the Johns Hopkins Hospital. 1964, 114, pp. 402-414.
Individual evidence
- ↑ Jutta Gärtner, Hugo Moser, David Valle: Mutations in the 70K peroxisomal membrane protein gene in Zellweger syndrome. In: Nature Genetics. 1, 1992, p. 16, doi : 10.1038 / ng0492-16 .
- ↑ Peroxisome biogenesis defect. In: Orphanet (Rare Disease Database).
