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Glycosylphosphatidylinositol biosynthesis defect 18(GPIBD18; DEE95)

MedGen UID:
1648478
Concept ID:
C4748357
Disease or Syndrome
Synonym: DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 95
 
Gene (location): PIGS (17q11.2)
 
Monarch Initiative: MONDO:0029140
OMIM®: 618143

Definition

Developmental and epileptic encephalopathy-95 (DEE95) is a severe autosomal recessive disorder characterized by severely impaired global development, hypotonia, weakness, ataxia, coarse facial features, and intractable seizures. More variable features may include abnormalities of the hands and feet, inguinal hernia, and feeding difficulties. The disorder is part of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway (summary by Nguyen et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). [from OMIM]

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Single transverse palmar crease
MedGen UID:
96108
Concept ID:
C0424731
Finding
The distal and proximal transverse palmar creases are merged into a single transverse palmar crease.
Short distal phalanx of finger
MedGen UID:
326590
Concept ID:
C1839829
Finding
Short distance from the end of the finger to the most distal interphalangeal crease or the distal interphalangeal joint flexion point. That is, hypoplasia of one or more of the distal phalanx of finger.
Short 4th metacarpal
MedGen UID:
327074
Concept ID:
C1840309
Finding
Short fourth metacarpal bone.
Short fourth metatarsal
MedGen UID:
336358
Concept ID:
C1848514
Finding
Short fourth metatarsal bone.
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
Short digit
MedGen UID:
893063
Concept ID:
C4023124
Finding
One or more digit that appears disproportionately short compared to the hand/foot, whereby either the entire digit or a specific phalanx is shortened.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Thickened helices
MedGen UID:
325240
Concept ID:
C1837732
Finding
Increased thickness of the helix of the ear.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Status epilepticus is a type of prolonged seizure resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Inappropriate laughter
MedGen UID:
98407
Concept ID:
C0424304
Finding
Laughing that may be excessive and/or inappropriate in context (e.g., laughing at a funeral while others are crying).
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Cerebellar vermis atrophy
MedGen UID:
149271
Concept ID:
C0742028
Disease or Syndrome
Wasting (atrophy) of the vermis of cerebellum.
Focal-onset seizure
MedGen UID:
199670
Concept ID:
C0751495
Disease or Syndrome
A focal-onset seizure is a type of seizure originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and may originate in subcortical structures.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Inappropriate crying
MedGen UID:
810697
Concept ID:
C0860609
Sign or Symptom
Uncontrolled episodes of crying occur without any apparent motivating stimuli.
Severe global developmental delay
MedGen UID:
332436
Concept ID:
C1837397
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
Hypoplasia of the pons
MedGen UID:
341246
Concept ID:
C1848529
Finding
Underdevelopment of the pons.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
EEG with burst suppression
MedGen UID:
369943
Concept ID:
C1969156
Finding
The burst suppression pattern in electroencephalography refers to a characteristic periodic pattern of low voltage (<10 microvolts) suppressed background and a relatively shorter pattern of higher amplitude slow, sharp, and spiking complexes.
Multifocal seizures
MedGen UID:
482664
Concept ID:
C3281034
Finding
Seizures that start from several different areas of the brain (i.e., with multiple ictal onset locations).
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
Protrusion of the contents of the abdominal cavity through the inguinal canal.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Multiple joint contractures
MedGen UID:
57633
Concept ID:
C0158118
Acquired Abnormality
Pectus carinatum
MedGen UID:
57643
Concept ID:
C0158731
Finding
A deformity of the chest caused by overgrowth of the ribs and characterized by protrusion of the sternum.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Low alkaline phosphatase
MedGen UID:
349734
Concept ID:
C1860130
Finding
Abnormally reduced serum levels of alkaline phosphatase.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.
Cystic hygroma
MedGen UID:
60195
Concept ID:
C0206620
Neoplastic Process
A cystic lymphatic lesion of the neck.
Gingival overgrowth
MedGen UID:
87712
Concept ID:
C0376480
Finding
Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.
Deep philtrum
MedGen UID:
374311
Concept ID:
C1839797
Finding
Accentuated, prominent philtral ridges giving rise to an exaggerated groove in the midline between the nasal base and upper vermillion border.
Long nose
MedGen UID:
326583
Concept ID:
C1839798
Finding
Distance from nasion to subnasale more than two standard deviations above the mean, or alternatively, an apparently increased length from the nasal root to the nasal base.
Widely spaced teeth
MedGen UID:
337093
Concept ID:
C1844813
Finding
Increased spaces (diastemata) between most of the teeth in the same dental arch.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Highly arched eyebrow
MedGen UID:
358357
Concept ID:
C1868571
Finding
Increased height of the central portion of the eyebrow, forming a crescent, semicircular, or inverted U shape.
Short chin
MedGen UID:
784514
Concept ID:
C3697248
Finding
Decreased vertical distance from the vermilion border of the lower lip to the inferior-most point of the chin.
Vertical forehead creases
MedGen UID:
869038
Concept ID:
C4023456
Anatomical Abnormality
Vertical soft tissue creases in the midline of the forehead, often extending from the hairline to the brow, and seen with facial expression or when the face is at rest.
Preauricular skin tag
MedGen UID:
395989
Concept ID:
C1860816
Finding
A rudimentary tag of skin often containing ear tissue including a core of cartilage and located just anterior to the auricle (outer part of the ear).
Fetal akinesia deformation sequence 1
MedGen UID:
220903
Concept ID:
C1276035
Disease or Syndrome
Decreased fetal activity associated with multiple joint contractures, facial anomalies and pulmonary hypoplasia. Ultrasound examination may reveal polyhydramnios, ankylosis, scalp edema, and decreased chest movements (reflecting pulmonary hypoplasia).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Recent clinical studies

Etiology

Xiao W, Huang Q, Luo P, Tan X, Xia H, Wang S, Sun Y, Wang Z, Ma Y, Zhang J, Jin Y
Sci Rep 2023 Oct 3;13(1):16642. doi: 10.1038/s41598-023-43189-5. PMID: 37789017Free PMC Article
Kang M, Wu M, Crane JL
Bone 2023 Jul;172:116778. Epub 2023 Apr 21 doi: 10.1016/j.bone.2023.116778. PMID: 37088336Free PMC Article
Sogabe H, Nangaku M, Ishibashi Y, Wada T, Fujita T, Sun X, Miwa T, Madaio MP, Song WC
J Immunol 2001 Sep 1;167(5):2791-7. doi: 10.4049/jimmunol.167.5.2791. PMID: 11509624
Nissen C, Tichelli A, Gratwohl A, Warthmann C, Moser Y, dalle Carbonare V, Sendelov S, Chklovskaia E, Jansen W, Wodnar-Filipowicz A, Sadallah S, Speck B
Acta Haematol 1999;101(4):165-72. doi: 10.1159/000040948. PMID: 10436296

Diagnosis

Pagnamenta AT, Murakami Y, Taylor JM, Anzilotti C, Howard MF, Miller V, Johnson DS, Tadros S, Mansour S, Temple IK, Firth R, Rosser E, Harrison RE, Kerr B, Popitsch N; DDD Study, Kinoshita T, Taylor JC, Kini U
Eur J Hum Genet 2017 Jun;25(6):669-679. Epub 2017 Mar 22 doi: 10.1038/ejhg.2017.32. PMID: 28327575Free PMC Article
Sato K, Noda Y, Yoda K
Mol Biol Cell 2007 Sep;18(9):3472-85. Epub 2007 Jul 5 doi: 10.1091/mbc.e07-03-0258. PMID: 17615295Free PMC Article
Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS
Br J Haematol 2001 Dec;115(4):1015-22. doi: 10.1046/j.1365-2141.2001.03191.x. PMID: 11843844
Nissen C, Tichelli A, Gratwohl A, Warthmann C, Moser Y, dalle Carbonare V, Sendelov S, Chklovskaia E, Jansen W, Wodnar-Filipowicz A, Sadallah S, Speck B
Acta Haematol 1999;101(4):165-72. doi: 10.1159/000040948. PMID: 10436296

Therapy

Kang M, Wu M, Crane JL
Bone 2023 Jul;172:116778. Epub 2023 Apr 21 doi: 10.1016/j.bone.2023.116778. PMID: 37088336Free PMC Article
Nissen C, Tichelli A, Gratwohl A, Warthmann C, Moser Y, dalle Carbonare V, Sendelov S, Chklovskaia E, Jansen W, Wodnar-Filipowicz A, Sadallah S, Speck B
Acta Haematol 1999;101(4):165-72. doi: 10.1159/000040948. PMID: 10436296

Prognosis

Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS
Br J Haematol 2001 Dec;115(4):1015-22. doi: 10.1046/j.1365-2141.2001.03191.x. PMID: 11843844

Clinical prediction guides

Pagnamenta AT, Murakami Y, Taylor JM, Anzilotti C, Howard MF, Miller V, Johnson DS, Tadros S, Mansour S, Temple IK, Firth R, Rosser E, Harrison RE, Kerr B, Popitsch N; DDD Study, Kinoshita T, Taylor JC, Kini U
Eur J Hum Genet 2017 Jun;25(6):669-679. Epub 2017 Mar 22 doi: 10.1038/ejhg.2017.32. PMID: 28327575Free PMC Article
Maydan G, Noyman I, Har-Zahav A, Neriah ZB, Pasmanik-Chor M, Yeheskel A, Albin-Kaplanski A, Maya I, Magal N, Birk E, Simon AJ, Halevy A, Rechavi G, Shohat M, Straussberg R, Basel-Vanagaite L
J Med Genet 2011 Jun;48(6):383-9. Epub 2011 Apr 14 doi: 10.1136/jmg.2010.087114. PMID: 21493957
Sogabe H, Nangaku M, Ishibashi Y, Wada T, Fujita T, Sun X, Miwa T, Madaio MP, Song WC
J Immunol 2001 Sep 1;167(5):2791-7. doi: 10.4049/jimmunol.167.5.2791. PMID: 11509624
Nissen C, Tichelli A, Gratwohl A, Warthmann C, Moser Y, dalle Carbonare V, Sendelov S, Chklovskaia E, Jansen W, Wodnar-Filipowicz A, Sadallah S, Speck B
Acta Haematol 1999;101(4):165-72. doi: 10.1159/000040948. PMID: 10436296
Chiaradonna F, Fontana L, Iavarone C, Carriero MV, Scholz G, Barone MV, Stoppelli MP
EMBO J 1999 Jun 1;18(11):3013-23. doi: 10.1093/emboj/18.11.3013. PMID: 10357814Free PMC Article

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