A number sign (#) is used with this entry because congenital disorder of glycosylation type Ip (CDG1P) is caused by homozygous or compound heterozygous mutation in the ALG11 gene (613666) on chromosome 13q14.

For a discussion of the classification of CDGs, see CDG1A (212065).

Rind et al. (2010) reported 2 sibs, born of consanguineous Turkish parents, with a multisystem metabolic disorder characterized by hypotonia, seizures, developmental retardation, and death by age 2 years. The first affected child showed poor feeding, recurrent vomiting, and muscular hypotonia in the first weeks of life. Other features included seizures, instability of body temperature, delayed pupil reaction and fixation, no blink reflex, and abnormal brainstem auditory response consistent with deafness. Dysmorphic features, including small head, high forehead with low hairline, and inverted nipples, were also noted. She died at age 2 years. The second affected child showed a similar disease course with hypotonia, generalized epilepsy, and opisthotonus. Dysmorphic features were not noted. Isoelectric focusing of serum transferrin from patient fibroblasts showed an increased amount of di- and asialo-transferrin with a decrease of tetrasialo-transferrin, consistent with CDG type I. Further studies showed an accumulation of shortened dolichol-linked oligosaccharides, indicating a defect at the step adding the fourth and fifth mannose residues.

Thiel et al. (2012) reported 3 unrelated patients with CDG1P. All had severely delayed psychomotor development and mental retardation with onset in the first year of life. Communication was absent, and social interaction very limited. All also had seizures and strabismus. Two had axial hypotonia and peripheral hypertonia. The most severely affected child had dysmorphic features, including long philtrum, retrognathia, and high forehead, scoliosis, fat pads, inverted nipples, oscillations of body temperature, dry scaly skin, and lack of visual tracking or light response. None were deaf. Biochemical analysis showed a CDG type I pattern. However, the pathologic glycosylation phenotype was only apparent after glucose starvation in patient fibroblasts; then, analysis of dolichol-linked oligosaccharides led to the emergence of pathologic shortened intermediate dolichol-linked oligosaccharides, indicating a defect in biosynthesis.

Haanpaa et al. (2019) reported 2 unrelated patients with CDG1P. The first patient (CDG-0455) was a 29-month-old girl of mixed European heritage with global developmental delay, hypotonia, and a history of poor weight gain necessitating G-tube placement and infantile spasms. She was nondysmorphic and had inverted nipples on physical examination. Her EEG showed modified hypsarrhythmia and bilateral spikes, which was consistent with infantile spasms. Brain MRI showed reduced diffusion of the periventricular parietal and temporal white matter and the splenium of the corpus callosum. Two carbohydrate-deficient transferrin analyses by electrospray ionization mass spectrometry (ESI-MS) were normal. The second patient (CDG-0358) was a 14-year-old Hispanic boy with a history of myoclonic epilepsy, global developmental delay, hypertonia, and microcephaly. MRI and CT scans of the brain were normal, but an EEG was abnormal. CDG screening by ESI-MS showed a profile suggestive of type I CDG. Testing of lipid-linked oligosaccharides on fibroblasts from both patients showed glycans truncated to a size that was consistent with ALG11 deficiency. Patient fibroblasts also showed abnormal truncation of GP130 (600694) isoforms and reduced ALG11 protein expression

The transmission pattern of CDG1P in the family reported by Rind et al. (2010) was consistent with autosomal recessive inheritance.

In 2 Turkish sibs, born of consanguineous parents, with congenital disorder of glycosylation type Ip, Rind et al. (2010) identified a homozygous mutation (L86S; 613666.0001) in the ALG11 gene.

In 3 unrelated patients with CDG1P, Thiel et al. (2012) identified compound heterozygous or homozygous mutations in the ALG11 gene (613666.0002-613666.0006). All mutations occurred in conserved residues, and the cellular biochemical defects could be rescued by retroviral complementation with wildtype ALG11. Glucose starvation prior to metabolic labeling of patient-derived fibroblasts was a crucial step for the correct biochemical diagnosis.

In 2 unrelated patients with CDG1P, Haanpaa et al. (2019) identified compound heterozygous mutations in the ALG11 gene (see 613666.0007-613666.0009). The mutations, which were identified by whole-exome sequencing or gene-specific deletion/duplication analysis, segregated with the disorder in both families. Haanpaa et al. (2019) found reduced ALG11 protein expression and evidence for a glycosylation defect in fibroblasts from both patients.