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PMM2-CDG (CDG I a) – Latest Evidence
This part of the document will be changed in the first revision, in which the level of evidence will
be displayed throughout this care pathway.
Congenital Disorder of Glycosylation: PMM 2-CDG (CDG 1a)
Congenital disorders of glycosylation (CDG) are a rapidly enlarging group of (neuro)metabolic
disorders. PMM2-CDG (CDG 1a), the most frequent CDG subtype, is due to a deficiency of PMM2
(
EC 5.4.2.28). Phosphomannomutase (PMM) catalyzes the second committed step in the synthesis
of GDP-mannose by conversion of mannose-6-phosphate to mannose-1-phosphate. Deficiency of
PMM leads to an early disruption of N-glycan assembly of glycoprotein causing hypoglycosylation
and hence deficiency and/or dysfunction of numerous glycoproteins, including serum proteins,
lysosomale enzymes and membrane glycoproteins.
4,5
The incidence is estimated at 1:20.000 - 1:80.000.
4,6,7
PMM2-CDG is inherited as an autosomal
recessive trait. The gene for phosphomannomutose 2 (PMM2) is located at chromosome 16p13.
4,8,9
Clinical features
PMM2-CDG is a multisystem disorder with highly variable phenotype. The combination and
severity of different signs and symptoms can vary widely, even between monozygotic symptoms.
5,8
Clinical presentation comprises three main features: moderate to severe neurologic disease,
more or less typical dysmorphy and variable involvement of different organs.
The nervous system is affected in all patients and most other organs are involved in a variable way.
4,10
The typical clinical course has been divided into an infantile multisystem stage, a childhood
ataxia-mental retardation stage and adult hypogonadal-stable disability stage.
9,11
Furthermore CDG 1a could be divided into two subtypes: a neurologic form with psychomotor
retardation, ataxia, strabismus and neonatal hypotonia and a multivisceral form with neurological
and extraneurological manifestations including liver, cardiac, renal or gastro-intestinal
involvement.
12
The purely neurologic form is generally not fatal, whereas the mortality of patients
with the multivisceral form is as high as 20%. Lethality, generally in the first years of life, is often
due to multi-organ failure, infantile catastrophic phase, or severe infection.
Infantile multisystem stage
Most patients are born at term after an uneventful pregnancy with a normal birth weight.
Dysmorphic features can be present at birth, including esotropia abnormal subcutaneous fat
distribution (fat pads, peau d’orange), inverted nipples and large (dysplastic) ears.
5,10
Infants often show axial hypotonia, hyporeflexia and developmental delay. Ataxia can occur as
result of cerebellar atrophy. Seizures may occur as early as the second year, but are usually
responsive to antiepileptic drugs
9
.
Feeding problems, frequent vomiting, diarrhea and subsequently failure to thrive are common and
may require gastrotomy or nasogastric tube feeding.
4,8,9
Cardiac disorders, such as cardiac effusion and cardiomyopathy can arise. Liver involvement
consists of hepatomegaly and increased transaminases. Kidneys may be enlarged and microcysts
and increased cortical echogenicity can be seen at renal ultrasound. Nephrotic syndrome has been
reported.
5,9
Albumin and coagulation factors are often decreased leading to edema and coagulopathy
respectively. Hypothyroidism is sometimes found through newborn screening
8
.
Osteopenia is common and remains throughout life
9
.
Infantile catastrophic phase often comprising hypoalbuminemia, anasarca, respiratory distress and
even heart failure may be provoked by infections
9
.
Pericardial fluid accumulation, generalized
edema and ascites has been observed in young children, with a risk of life-threatening extra