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GM3 synthase deficiency(SPDRS)

MedGen UID:
323005
Concept ID:
C1836824
Disease or Syndrome
Synonyms: Salt and pepper developmental regression syndrome; SALT AND PEPPER MENTAL RETARDATION SYNDROME; Salt and pepper syndrome; SPDRS
SNOMED CT: GM3 synthase deficiency (722762005); Ganglioside GM3 synthase deficiency (722762005); Amish infantile epilepsy syndrome (722762005); Infantile-onset symptomatic epilepsy syndrome (722762005)
 
Gene (location): ST3GAL5 (2p11.2)
 
Monarch Initiative: MONDO:0018274
OMIM®: 609056
Orphanet: ORPHA370933

Definition

Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterized by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss (summary by Fragaki et al., 2013). Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood (summary by Boccuto et al., 2014). Not all patients have overt seizures (Lee et al., 2016). [from OMIM]

Additional description

From MedlinePlus Genetics
GM3 synthase deficiency is characterized by recurrent seizures (epilepsy) and problems with brain development. Within the first few weeks after birth, affected infants become irritable and develop feeding difficulties and vomiting that prevent them from growing and gaining weight at the usual rate. Seizures begin within the first year of life and worsen over time. Multiple types of seizures are possible, including generalized tonic-clonic seizures (also known as grand mal seizures), which cause muscle rigidity, convulsions, and loss of consciousness. Some affected children also experience prolonged episodes of seizure activity called nonconvulsive status epilepticus. The seizures associated with GM3 synthase deficiency tend to be resistant (refractory) to treatment with antiseizure medications.

GM3 synthase deficiency profoundly disrupts brain development. Most affected children have severe intellectual disability and do not develop skills such as reaching for objects, speaking, sitting without support, or walking. Some have involuntary twisting or jerking movements of the arms that are described as choreoathetoid. Although affected infants can likely see and hear at birth, vision and hearing become impaired as the disease worsens. It is unknown how long people with GM3 synthase deficiency usually survive.

Some affected individuals have changes in skin coloring (pigmentation), including dark freckle-like spots on the arms and legs and light patches on the arms, legs, and face. These changes appear in childhood and may become more or less apparent over time. The skin changes do not cause any symptoms, but they can help doctors diagnose GM3 synthase deficiency in children who also have seizures and delayed development.  https://medlineplus.gov/genetics/condition/gm3-synthase-deficiency

Clinical features

From HPO
Hyporeflexia of upper limbs
MedGen UID:
323007
Concept ID:
C1836835
Finding
Reduced intensity of muscle tendon reflexes in the upper limbs. Reflexes are elicited by stretching the tendon of a muscle, e.g., by tapping.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
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.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Global brain atrophy
MedGen UID:
66840
Concept ID:
C0241816
Pathologic Function
Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size.
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.
Lower limb hyperreflexia
MedGen UID:
322973
Concept ID:
C1836696
Finding
Developmental stagnation at onset of seizures
MedGen UID:
324612
Concept ID:
C1836829
Finding
A cessation of the development of a child in the areas of motor skills, speech and language, cognitive skills, and social and/or emotional skills, following the onset of epilepsy.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Multifocal epileptiform discharges
MedGen UID:
866864
Concept ID:
C4021219
Finding
An abnormality in cerebral electrical activity recorded along the scalp by electroencephalography (EEG) and being identified at multiple locations (foci).
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Hypermelanotic macule
MedGen UID:
375013
Concept ID:
C1842774
Finding
A hyperpigmented circumscribed area of change in normal skin color without elevation or depression of any size.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Visual loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that).
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVGM3 synthase deficiency
Follow this link to review classifications for GM3 synthase deficiency in Orphanet.

Recent clinical studies

Etiology

Bowser LE, Young M, Wenger OK, Ammous Z, Brigatti KW, Carson VJ, Moser T, Deline J, Aoki K, Morlet T, Scott EM, Puffenberger EG, Robinson DL, Hendrickson C, Salvin J, Gottlieb S, Heaps AD, Tiemeyer M, Strauss KA
Mol Genet Metab 2019 Apr;126(4):475-488. Epub 2019 Jan 21 doi: 10.1016/j.ymgme.2019.01.013. PMID: 30691927
Wang H, Wang A, Wang D, Bright A, Sency V, Zhou A, Xin B
Clin Genet 2016 May;89(5):625-9. Epub 2016 Jan 20 doi: 10.1111/cge.12703. PMID: 26649472

Diagnosis

Dookwah M, Wagner SK, Ishihara M, Yu SH, Ulrichs H, Kulik MJ, Zeltner N, Dalton S, Strauss KA, Aoki K, Steet R, Tiemeyer M
Hum Mol Genet 2023 Dec 1;32(24):3323-3341. doi: 10.1093/hmg/ddad146. PMID: 37676252Free PMC Article
Watanabe S, Lei M, Nakagawa E, Takeshita E, Inamori KI, Shishido F, Sasaki M, Mitsuhashi S, Matsumoto N, Kimura Y, Iwasaki M, Takahashi Y, Mizusawa H, Migita O, Ohno I, Inokuchi JI
Brain Dev 2023 May;45(5):270-277. Epub 2023 Jan 21 doi: 10.1016/j.braindev.2023.01.002. PMID: 36690566
Inamori KI, Inokuchi JI
Int J Mol Sci 2022 May 11;23(10) doi: 10.3390/ijms23105368. PMID: 35628171Free PMC Article
Wang H, Bright A, Xin B, Bockoven JR, Paller AS
Am J Med Genet A 2013 Apr;161A(4):875-9. Epub 2013 Feb 22 doi: 10.1002/ajmg.a.35826. PMID: 23436467
Fragaki K, Ait-El-Mkadem S, Chaussenot A, Gire C, Mengual R, Bonesso L, Bénéteau M, Ricci JE, Desquiret-Dumas V, Procaccio V, Rötig A, Paquis-Flucklinger V
Eur J Hum Genet 2013 May;21(5):528-34. Epub 2012 Sep 19 doi: 10.1038/ejhg.2012.202. PMID: 22990144Free PMC Article

Therapy

Yang H, Brown RH Jr, Wang D, Strauss KA, Gao G
Trends Mol Med 2021 Jun;27(6):520-523. Epub 2021 Mar 10 doi: 10.1016/j.molmed.2021.02.004. PMID: 33714697Free PMC Article

Prognosis

Watanabe S, Lei M, Nakagawa E, Takeshita E, Inamori KI, Shishido F, Sasaki M, Mitsuhashi S, Matsumoto N, Kimura Y, Iwasaki M, Takahashi Y, Mizusawa H, Migita O, Ohno I, Inokuchi JI
Brain Dev 2023 May;45(5):270-277. Epub 2023 Jan 21 doi: 10.1016/j.braindev.2023.01.002. PMID: 36690566

Clinical prediction guides

Bowser LE, Young M, Wenger OK, Ammous Z, Brigatti KW, Carson VJ, Moser T, Deline J, Aoki K, Morlet T, Scott EM, Puffenberger EG, Robinson DL, Hendrickson C, Salvin J, Gottlieb S, Heaps AD, Tiemeyer M, Strauss KA
Mol Genet Metab 2019 Apr;126(4):475-488. Epub 2019 Jan 21 doi: 10.1016/j.ymgme.2019.01.013. PMID: 30691927
Fragaki K, Ait-El-Mkadem S, Chaussenot A, Gire C, Mengual R, Bonesso L, Bénéteau M, Ricci JE, Desquiret-Dumas V, Procaccio V, Rötig A, Paquis-Flucklinger V
Eur J Hum Genet 2013 May;21(5):528-34. Epub 2012 Sep 19 doi: 10.1038/ejhg.2012.202. PMID: 22990144Free PMC Article

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