GM27955
LCL from B-Lymphocyte
Description:
CEREBRAL CREATINE DEFICIENCY SYNDROME 3; CCDS3
AGAT DEFICIENCY
L-ARGININE:GLYCINE AMIDINOTRANSFERASE; GATM
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases
PIGI Consented Sample |
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Biopsy Source
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Peripheral vein
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Cell Type
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B-Lymphocyte
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Tissue Type
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Blood
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Transformant
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Epstein-Barr Virus
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Sample Source
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LCL from B-Lymphocyte
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Race
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Asian
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Ethnicity
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Not Hispanic/Latino
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Ethnicity
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Taiwanese
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Country of Origin
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USA
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Family History
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N
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Relation to Proband
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proband
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Confirmation
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Molecular characterization before cell line submission to CCR
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| Gene |
GATM |
| Chromosomal Location |
15q21.1 |
| Allelic Variant 1 |
602360.0004; CEREBRAL CREATINE DEFICIENCY SYNDROME 3,
AGAT DEFICIENCY |
| Identified Mutation |
IVS3+1G>T (c.484+1G>T); In a Chinese girl with cerebral creatine deficiency syndrome-3 (CCDS3; 612718), Ndika et al. (2012) identified a homozygous G-to-T transversion in intron 3 of the GATM gene (c.484+1G-T), resulting in a splice site and a truncated protein lacking exon 3 (Ala97ValfsTer11). The mutant transcript was subject to nonsense-mediated mRNA decay. Each unaffected parent was heterozygous for the mutation. GATM activity was not detectable in patient cells. The patient showed significant developmental progress after early and intense treatment with creatine supplementation. |
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| Gene |
GATM |
| Chromosomal Location |
15q21.1 |
| Allelic Variant 2 |
602360.0004; CEREBRAL CREATINE DEFICIENCY SYNDROME 3,
AGAT DEFICIENCY |
| Identified Mutation |
IVS3+1G>T (c.484+1G>T); In a Chinese girl with cerebral creatine deficiency syndrome-3 (CCDS3; 612718), Ndika et al. (2012) identified a homozygous G-to-T transversion in intron 3 of the GATM gene (c.484+1G-T), resulting in a splice site and a truncated protein lacking exon 3 (Ala97ValfsTer11). The mutant transcript was subject to nonsense-mediated mRNA decay. Each unaffected parent was heterozygous for the mutation. GATM activity was not detectable in patient cells. The patient showed significant developmental progress after early and intense treatment with creatine supplementation. |
| Demographic Data |
| Relation to Proband |
proband |
| Age at Sampling |
18 YR |
| Sex |
Female |
| Age of Onset(If not a control) |
4 MO |
| Age at Diagnosis(If not a control) |
16 MO |
| Hispanic or Latino/Not Hispanic or Latino |
Not Hispanic/Latino |
| Racial Category |
Asian |
| Country |
USA |
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| Data Elements |
| Clinical Element Type: General NIGMS Catalog Remarks |
| (Baseline) |
| Mutation Information |
| Gene, variant, consequence, and exon number: |
HOMOZYGOUS MUTATION IN THE DONOR SPLICE SITE OF EXON 3 OF GATM: IVS3+1G>T (C.484+1G>T; W194X) RESULTING IN SKIPPING OF EXON 3 (R.289_484DEL196) |
| Zygosity: |
Homozygous
Notes: HOMOZYGOUS VARIANT INHERITED FROM BOTH MOTHER AND FATHER, EACH HETEROZYGOUS FOR THE VARIANT |
| Age of Symptom Onset and Age at Diagnosis |
| Age of Symptom Onset: |
4 MONTHS |
| Age at Diagnosis: |
16 MONTHS; DIAGNOSED BY A GENETICIST |
| In Utero History Information |
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| Additional Information: |
BORN AT TERM; UNEVENTFUL PREGNANCY |
| Birth History Information |
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Failure to thrive
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| Additional Information: |
AT 4 MONTHS, FAILURE TO THRIVE HAD RESOLVED AND CURRENTLY PHENOTYPE IS NORMAL |
| Dysmorphic Features |
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| Additional Information: |
AT 12 YEARS: SHORT STATURE, DELAYED GROWTH AND PUBERTY |
| Neurological Symptoms |
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Hypotonia
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| Optical and Audiological Symptoms |
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Defective vision
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| Additional Information: |
MYOPIA |
| Musculoskeletal Symptoms |
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| Developmental Milestones |
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Delayed speech and language development
Global developmental delay
Delayed gross motor skills
Abnormal weight for age
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| Additional Information: |
MILD TO MODERATE GLOBAL DEVELOPMENTAL DELAY; POOR WEIGHT GAIN AT 10 MONTHS; AT 3 YEARS DELAY IN COMPREHENSIVE AND EXPRESSIVE LANGUAGE SKILLS; AT 13 YEARS SPEECH PROCESSING DISORDER; AT 19 YEARS EXCELS ACADEMICALLY, NO PHYSICAL LIMITATIONS, NORMAL SPEECH |
| Gastrointestinal Symptoms |
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| Genitourinary Symptoms |
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| Respiratory and Cardiovascular Symptoms |
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| Cognitive and Behavioral Symptoms |
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| Additional Information |
| Testing Performed |
| Neurological Testing: |
AT 2 YEARS, MRI: NORMAL; AT 2 AND 11 YEARS, MRS: CREATINE TO NAA RATIO 50-60% OF NORMAL WITHIN THALAMUS AND BASAL GANGLIA WITH MILDLY DECREASED RATIO COMPARED TO AGE-MATCHED CONTROLS |
| Metabolic, Hematologic, and Endocrinologic Testing: |
INBORN ERROR OF METABOLISM; AT 10 MONTHS, URINE AMINO ACIDS NORMAL, EXTREMELY LOW LEVELS OF URINE AND PLASMA GUANIDINOACETATE (PLASMA 0.07 UMOL/L) AND PLASMA CREATINE (2.3 UMOL/L); AT 2 YEARS, GENERALIZED ORGANIC ACIDURIA (ORGANIC ACID CONCENTRATIONS RANGED 2-5X THE UPPER LIMITS OF NORMAL), LOW CREATINE, GATM LEVEL NOT DETECTABLE; NORMAL RENAL ULTRASOUNDS; AT 12 YEARS, BUN, CREATINE, AND ELECTROLYTES NORMAL EXCEPT FOR SLIGHTLY LOW CO2 OF 23; 1H-MRS AT 2 YEARS SHOWED COMPLETE ABSENCE OF CREATINE PEAK, AND SEQUENTIAL BRAIN MRS REVEALED RECOVERY OF CEREBRAL CREATINE LEVEL TO 80-90% OF NORMAL AFTER 23 MONTHS OF ORAL CREATINE SUPPLEMENTATION; AT 2 YEARS GATM ACTIVITY NOT DETECTABLE, ARGININE GLYCINE AMIDINOTRANSFERASE ACTIVITY NOT DETECTABLE |
| Uncategorized Testing: |
NORMAL KARYOTYPE: 46,XX; NORMAL KIDNEY FUNCTION TESTS |
| Treatments and Assistive Devices |
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Occupational therapy
Physical therapy
Speech therapy
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| Additional Testing: |
SPEECH THERAPY AT 27 MONTHS TO 9 YEARS OF AGE |
| Medications |
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CREATINE 200-800 MG/KG/D, CURRENTLY ~515 MG/KG/D |
| Family History |
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THE DONORS PARENTS (NOT IN REPOSITORY) ARE HETEROZYGOUS FOR THE MUTATION IN GATM: IVS3+1G>T. |
| Remarks |
See Phenotypic Data tab. Same subject as GM28589 (iPSC). |
| Portales-Castillo I, Singal R, Ambrose A, Song JH, Son M, Goo YA, Zhou W, Traum AZ, Coler-Reilly A, Humphreys BD, Civitelli R, Jüppner H, Lundquist AL, Seres P, Allegretti AS, Mercimek-Andrews S, Reduced guanidinoacetate in plasma of patients with autosomal dominant Fanconi syndrome due to heterozygous P341L JIMD reports65:341-353 2024 |
| PubMed ID: 39544690 |
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| Stockler-Ipsiroglu S, Apatean D, Battini R, DeBrosse S, Dessoffy K, Edvardson S, Eichler F, Johnston K, Koeller DM, Nouioua S, Tazir M, Verma A, Dowling MD, Wierenga KJ, Wierenga AM, Zhang V, Wong LJ, Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide Molecular genetics and metabolism116:252-9 2015 |
| PubMed ID: 26490222 |
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| Ndika JD, Johnston K, Barkovich JA, Wirt MD, O'Neill P, Betsalel OT, Jakobs C, Salomons GS, Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency Molecular genetics and metabolism106:48-54 2011 |
| PubMed ID: 22386973 |
| Split Ratio |
1:5 |
| Temperature |
37 C |
| Percent CO2 |
5% |
| Percent O2 |
AMBIENT |
| Medium |
Roswell Park Memorial Institute Medium 1640 with 2mM L-glutamine or equivalent |
| Serum |
15% fetal bovine serum Not Inactivated |
| Substrate |
None specified |
| Subcultivation Method |
dilution - add fresh medium |
| Supplement |
- |
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