Including the two patients reported on in this article 10 patients from 6 different families carrying mutations in the PGAP1 gene have been described so far [2, 4–7]. A summary of the clinical and genetic findings is given in Table 1. In none of the patients the disorder had a progressive course instead the patients showed a varying degree of development. 8 patients were reported to have had muscular hypotonia in the neonatal period leading to feeding problems in 6. Tremor was observed in 3 patients, dyskinetic movements in 6. Only two patients have been reported to walk independently, however the majority of the patients were still young. Intellectual disability seems to be a constant feature but with varying severity. Only one patient has been reported to be able to speak. This patient was also the only normocephalic patient while the others were microcephalic indicating that he might be less severely affected. Epilepsy was present in three out of ten patients and one additional patient showed generalized slowing in the EEG without clear epileptiform changes. Recurred apneas especially during sleep, which were a very prominent symptom in the patients described in this article, have not been described in the other patients. Dysmorphic features described in the patients include large ears, a flattened nasal root [2], prominent forehead, large mouth, abnormal teeth, high arched eyebrows, a short neck [5], upward slanting palpebral fissures, deep-set eyes, large ear lobes and prominent helices and antihelices, extra mamelons of teeth and diminished enamel [6]. In addition to the face malformations Williams et al. described abnormal hand morphology in his patient. Metabolic analysis in the PGAP1 patients has overall yielded unremarkable results. Hyperphosphatasia that was described in other GPI-APs related disease (PIGV, PIGO and PGAP2) due to recognition of mannose residue in immature GPI and the consecutive cleavage of the hydrophobic signal peptide from the proproteins by GPI transamidase resulting in secretion of soluble alkaline phosphatase [8]. But serum levels of alkaline phosphatase were normal in our patients and in the Pgap1 mouse model as well, suggesting elevated alkaline phosphatase is not part of PGAP1 disease. Imaging of the brain was performed in 9 out of 10 patients (1 CT, 8 MRIs). Cerebral imaging revealed global brain atrophy in 5/9 patients, defective myelination in 4/9, abnormalities of the sylvian fissure in 2/9 and callosum agenesis and vermis hypoplasia in one. One patient, the only patient that was able to speak, was reported to have a normal MRI at the age of 5 years again supporting the milder course of the disease in this patient. The MRIs of the siblings from North Turkey were also described to be normal, but information of the patients’ age at investigation was not provided. Sequential MRIs, available in the patient described by Williams et al. and the two patients reported on in this article, demonstrate that the amount of myelin detected on MRI is increasing indicating delayed myelination rather than defective myelination. However, the analysis of the MT saturation maps shows that the amount of myelin is still decreased when compared to age matched controls at the age of 2 years. Single voxel proton MR spectroscopy also indicated a defect in the myelin.

	This Study		Murakami et al.		Bosch et al.	Williams et al.	Novarino et al.		Granzow et al.
	II-1	II-2	III-2	III-3			IV-3	IV-4	I-1	I-2
Family history	Dizygotic Caucasian twins of non-consanguineous parents		Sibling of consanguine Syrian relationship		non-consanguineous	non-consanguineous	consanguineos/1° cousins		consanguineos/1° cousins
Genotype	c.334_335InsA (p.Arg112fs)		homozygous c.589_591del (p.Leu197del)		c.274_276del (p.Pro92del)	c.1572 T > A (p.Tyr524*)	homozygous splice site mutation c.1952 + 1G > T		homozygous splice site mutation c.1090-2A > G
	AND				AND	AND
	splice site mutation c.1173G > C (p.Leu391Leu)				c.921_925del (p.Lys308Asnfs*25)	c.1396C > T p.(Gln466*)
Gender	M	M	F	M	M	M	M	M	M	F
Agea	2	2	4 5/12	2 9/12	7 10/12	3	6 6/12	9/12	8	4
Pregnancy/Birth	30th weeks, maternal HELLP syndrome		unremarkable		planned CS, 38 weeks	39 weeks	NA	NA	unremarkable
Facial dysmorphisms	(+)	(+)	+	+	+	+	-	-	-	-
Microcephaly	+	+	+	+	-	+	NA	NA	+	+
Intellectual disability	+	+	IQ < 35	IQ < 35	IQ 49	+	+	-	+	+
Speech	Babble	Babble	Babble	NA	2 6/12	delayed	NA	NA	-	-
Motor developmental delay	+	+	+	+	+	+	+	-	+	+
Walking independently (years)	-	-	4 5/12	-	2 6/12	-	NA	NA	NA	-
Hypotonia	+	+	+	+	+	+	NA	NA	+	+
Neuropathy/Spasticity	-	-	NA	NA	-	-	+	+	-	+
Stereotypic/dyskinetic movements	-	-	+	+	-	+	+	+	+	-
Eating/Feeding	Milk bottles	Milk bottles	Milk bottles	Milk bottles	-	G-tube feeding	NA	NA	-	Failure to thrive
Respiration	Recurrent apneas	Recurrent apneas	-	-	-	-	NA	NA	+	-
Ophthalmological findings	-	-	-	-	CVI	CVI	-	-	Retinal dystrophy (ERG)
Seizures/EEG abnormalities	−/−	+/+	+/NA	-/NA	-/NA	−/+	NA	NA	−/−	−/−
Imaging	Frontal accentuated brain atrophy and significant delayed myelination (MRI)		Brain atrophy (CT)	NA	Normal (MRI)	Thinning of thecorpus collosum, diminished white matter, prominence of the right posterior Sylvian fissure (MRI)	Prominent cortical sulci and widened sylvian fissures (MRI)	Corpus callosum agnesis, vermis hypoplasia, defective myelination (MRI)	Normal (MRI)	Normal (MRI)

CS caesarian section, CT computer tomography, CVI cortical visual impairment, EEG electroencephalogram, ERG electroretinogram, F female, IQ intelligence quotient, M male, MRI magnetic resonance imaging, NA not available

^a Age at investigation