Lesch-Nyhan Disease and Its Variants: Phenotypic and Mutation Spectrum of Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency in Argentine Patients

Laróvere, Laura E.; Fairbanks, Lynette D.; Jinnah, H. A.; Guelbert, Norberto B.; Escuredo, Emilia; Becerra, Adriana; Kremer, Raquel Dodelson de

doi:10.1590/2326-4594-JIEMS-2020-0027

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Journal of Inborn Errors of Metabolism and Screening

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Original Article • J. inborn errors metab. screen. 9 • 2021 • https://doi.org/10.1590/2326-4594-JIEMS-2020-0027 copy

Lesch-Nyhan Disease and Its Variants: Phenotypic and Mutation Spectrum of Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency in Argentine Patients

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a disorder of purine metabolism responsible for Lesch-Nyhan Disease (LND) and its variants, HPRT-related hyperuricemia with neurologic dysfunction (HND) and HPRT-related hyperuricemia (HRH). The objective of this study was to characterize a cohort of Argentine patients with HPRT deficiency diagnosed in a single center. Results: Twenty nine patients were studied, including 12 LND, 15 HND and 2 HRH. The average onset age was 0.64 years for LND with motor delay as the main manifestation, 8.84 years for HND and 2.5 years for HRH; nephrological manifestations predominated as presenting features in these variants. The average diagnosis age was 3.58 years for LND, 17.21 years for HND and 2.5 years for HRH. Clinical heterogeneity was more evident in HND, even in members of the same family. All patients presented hyperuricemia and no detectable HPRT activity in erythrocyte lysate. The molecular study allowed to identify 9 different mutations in HPRT1 gene from 24 patients (11 independent pedigrees) and to establish genotype-phenotype correlation. In conclusion, this study describes the genotypic/phenotypic spectrum of HPRT deficiency in Argentine patients and highlights the need to increase awareness about the suspicion of these diseases, especially the LND variants with high clinical heterogeneity.

Keywords
Hypoxanthine-guanine phosphoribosyltransferase deficiency; hyperuricemia; Lesch-Nyhan disease; Lesch-Nyhan variant; HPRT1 mutation

Case	Family	Age (diagnosis)	Blood UA¹ (diagnosis)	HPRT Activity²	Self-injury (onset)	Neurological dysfunction	Nephrological manifestations	Joint disease	Treatment
Lesch-Nyhan disease
1	1	5 years	11.0 mg/dl	<1	x (5 years)	Motor delay (6 months) Dystonia superimposed on hypotonia	Recurrent renal stones	-	Allopurinol Risperidone Folate SAM
2	2	10 years	8.1 mg/dl	<1	x (6 years)	Motor delay (8 months) Dystonic and ballismic movements at 1 year Epilepsy	Recurrent renal stones	-	Allopurinol Carbamazepine Clonazepam Folate
3	3	9 years	9.2 mg/dl	<1	x (8 years)	Motor delay (8 months) Dystonia Generalized hypotonia with hyperreflexia	Uric acid crystals	-	Allopurinol Clonazepam
4	4	11 months	9.8 mg/dl	<1	-	Spastic quadriplegia (10 months) Dystonia Axial hypotonia	-	-	Allopurinol
5	5	4 years	7.7 mg/dl	<1	x (8 years)	Motor delay (4 months) Dystonia Choreoathetosis	Kidney stones	-	Allopurinol Risperidone
6	5	3 years	8.2 mg/dl	<1	x (3 years)	Motor delay (7 months) Dystonia Choreoathetosis Generalized hypotonia with hyperreflexia	Kidney stones	-	Allopurinol Clonazepam
7	6	nd	nd	<1	x	Motor delay Dystonia Choreoathetosis	Nd	nd	nd
8	7	1 year	8.0 mg/dl	<1	x	Dystonic cerebral palsy	-	-	nd
9	8	2 years	12.5 mg/dl	<1	x (2 years)	Motor delay (5 months) Spastic-dystonic tetraparesis Microcephaly	-	-	nd
10	9	2 years	nd	<1	x (2 years)	Spastic quadriplegia	-	-	nd
11	9	2 years	nd	<1	x (2 years)	Spastic quadriplegia	-	-	nd
12	10	6 months	8 mg/dl	<1	-	Motor delay (5 months)	-	-	nd
HPRT-related hyperuricemia with neurologic dysfunction
13	11	9 years	9.0 mg/dl	<1	-	Motor delay (<1 year) Slightly slow gait Speech delay, slightly slow and indistinct Hypomimia Brisk leg reflexes, ankle clonus Significant cognitive impairment	-	-	Allopurinol
14	11	56 years	with allopurinol treatment	<1	-	Moderate dystonic dysarthria Slightly slow gait Brisk leg reflexes, peripheral neuropathy Mild cognitive impairment	Nephrolitiasis Renal insufficiency	Tophus on knee (28 years)	Allopurinol Glibencamide
15	11	37 years	with allopurinol treatment	<1	-	Motor delay (1.5 year) Slightly slow gait Moderate dystonic dysarthria Slow/clumsy hand movements; brisk arm and leg reflexes, neuropathy Mild cognitive impairment	Gout Nephrolithiasis	Recurrent tophi Joint deformities of the hands and feet	Allopurinol
16	12	20 years	11.5 mg/dl	<1	-	Psychomotor development retardation (<1 year) Slightly indistinct speech Normal gait but can´t edge-walking Slow/clumsy hand movements Brisk arm and leg reflexes, ankle clonus Severe cognitive impairment	Bilateral renal lithiasis	Asymmetric polyarthritis of hands, both knees, ankles and feet	Allopurinol
17	13	14 years	16.0 mg/dl	<1	-	Motor delay (2 years) Hypophonic speech Normal gait Slightly slowed hand movements Marked cognitive impairment	Renal insufficiency Nephrolitiasis	Tophi Joint deformities of the hands, feet, elbows	Allopurinol Enapril
18	13	19 years	14.6 mg/dl	<1	-	Normal speech and gait Minor overflow posturing of one hand Mild cognitive impairment	Gout (19 years)	Tophi	Allopurinol
19	13	15 years	13.8 mg/dl	<1	-	Mild cognitive impairment Speech and gait: nd	Renal insufficiency Nephrolitiasis	Uric acid crystal in finger (14 years) Tophi	Allopurinol
20	13	13 years	9.6 mg/dl	<1	-	Moderate cognitive impairment Speech and gait: nd	-	Tophi	Allopurinol
21	13	3 years	14.4 mg/dl	<1	-	Mild cognitive impairment Speech and gait: nd	Recurrent urinary infections (3 months) Nephrocalcinosis (10 months)	-	Allopurinol Iron supplement Folic acid Sodium bicarbonate
22	13	2 months³	8.5 mg/dl	<1	-	Mild cognitive impairment Speech and gait: nd	-	-	Allopurinol
23	13	7 days³	17.0 mg/dl	<1	-	nd	-	-	Allopurinol
24	13	21 years	19.0 mg/dl	<1	-	Moderate mental retardation Speech and gait: nd	Polycystic kidney disease (1 year) Chronic renal failure Kidney transplant	Tophi	Allopurinol
25	13	20 years	13.0 mg/dl	<1	-	Moderate mental retardation Speech and gait: nd	Kidney stones	Inflammation of the toe	Allopurinol Colchicine
26	13	24 years	14.0 mg/dl	<1	-	Moderate mental retardation Speech and gait: nd	nd	Tophus on ear Knee inflammation	Colchicine
27	14	9 years	17.3 mg/dl	<1	-	Mild cognitive impairment Speech and gait: nd	Acute renal failure (9 years)	-	Allopurinol
HPRT-related hyperuricemia
28	15	4 years	15.6 mg/dl	<1	-	-	Acute renal failure (4 years)	-	Allopurinol
29	15	1 year³	9.0 mg/dl	<1	-	-	-	-	Allopurinol

Case	Family	Phenotype	Mutation	Result	Remark	Prior reports
13	11	HND	c.143G>A	p.R48H		Laróvere et al., 2007[2525. Laróvere LE, O’Neill JP, Randall M, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):255-258. doi: 10.1080/15257770701257269 https://doi.org/10.1080/1525777070125726... ] Jinnah et al., 2010[2222. Jinnah HA, Ceballos-Picot I, Torres RJ, et al. Attenuated variants of Lesch-Nyhan disease. Brain. 2010;133(Pt 3):671-689. doi: 10.1093/brain/awq013 https://doi.org/10.1093/brain/awq013... ]
14	11	HND	c.143G>A	p.R48H		Laróvere et al., 2007[2525. Laróvere LE, O’Neill JP, Randall M, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):255-258. doi: 10.1080/15257770701257269 https://doi.org/10.1080/1525777070125726... ]
15	11	HND	c.143G>A	p.R48H		Laróvere et al., 2007[2525. Laróvere LE, O’Neill JP, Randall M, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):255-258. doi: 10.1080/15257770701257269 https://doi.org/10.1080/1525777070125726... ]
16	12	HND	c.143G>A	p.R48H		Sapag et al., 2012[2626. Sapag A, Frischling E, Laborde H. Hypoxanthine-guanine phosphoribosyltransferase deficiency in a patient with a Madrid II mutation. Joint Bone Spine. 2013;80(1):93-95. doi: 10.1016/j.jbspin.2012.06.020 https://doi.org/10.1016/j.jbspin.2012.06... ]
1	1	LND	c.203T>C	p.L68P		Jinnah et al., 2006[2727. Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain. 2006;129(Pt 5):1201-1217. doi: 10.1093/brain/awl056 https://doi.org/10.1093/brain/awl056... ] Laróvere el al., 2007[2525. Laróvere LE, O’Neill JP, Randall M, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):255-258. doi: 10.1080/15257770701257269 https://doi.org/10.1080/1525777070125726... ]
2	2	LND	c.209G>A	p.G70E	de novo	Jinnah et al., 2006[2727. Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain. 2006;129(Pt 5):1201-1217. doi: 10.1093/brain/awl056 https://doi.org/10.1093/brain/awl056... ] Laróvere et al., 2007[2525. Laróvere LE, O’Neill JP, Randall M, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):255-258. doi: 10.1080/15257770701257269 https://doi.org/10.1080/1525777070125726... ]
3	3	LND	212dupG	Frame shift in E3		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
28	15	HRH	c.485+5G>A	Exon 6 excluded		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
29	15	HRH	c.485+5G>A	Exon 6 excluded		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
4	4	LND	c.532+1G>A	Exon 7 excluded		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
17	13	HND	c.584A>C	p.Y195S		Laróvere et al., 2004[1919. Laróvere LE, Romero N, Fairbanks LD, et al. A novel missense mutation, c.584A > C (Y195S), in two unrelated Argentine patients with hypoxanthine-guanine phosphoribosyl-transferase deficiency, neurological variant. Mol Genet Metab. 2004;81(4):352-354. doi: 10.1016/j.ymgme.2004.01.013 https://doi.org/10.1016/j.ymgme.2004.01.... ] Laróvere et al., 2007[2525. Laróvere LE, O’Neill JP, Randall M, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):255-258. doi: 10.1080/15257770701257269 https://doi.org/10.1080/1525777070125726... ] Jinnah et al., 2010[2222. Jinnah HA, Ceballos-Picot I, Torres RJ, et al. Attenuated variants of Lesch-Nyhan disease. Brain. 2010;133(Pt 3):671-689. doi: 10.1093/brain/awq013 https://doi.org/10.1093/brain/awq013... ]
18	13	HND	c.584A>C	p.Y195S		Laróvere et al., 2004[1919. Laróvere LE, Romero N, Fairbanks LD, et al. A novel missense mutation, c.584A > C (Y195S), in two unrelated Argentine patients with hypoxanthine-guanine phosphoribosyl-transferase deficiency, neurological variant. Mol Genet Metab. 2004;81(4):352-354. doi: 10.1016/j.ymgme.2004.01.013 https://doi.org/10.1016/j.ymgme.2004.01.... ] Laróvere et al., 2007[2525. Laróvere LE, O’Neill JP, Randall M, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):255-258. doi: 10.1080/15257770701257269 https://doi.org/10.1080/1525777070125726... ] Jinnah et al., 2010[2222. Jinnah HA, Ceballos-Picot I, Torres RJ, et al. Attenuated variants of Lesch-Nyhan disease. Brain. 2010;133(Pt 3):671-689. doi: 10.1093/brain/awq013 https://doi.org/10.1093/brain/awq013... ]
19	13	HND	c.584A>C	p.Y195S		Laróvere et al., 2004[1919. Laróvere LE, Romero N, Fairbanks LD, et al. A novel missense mutation, c.584A > C (Y195S), in two unrelated Argentine patients with hypoxanthine-guanine phosphoribosyl-transferase deficiency, neurological variant. Mol Genet Metab. 2004;81(4):352-354. doi: 10.1016/j.ymgme.2004.01.013 https://doi.org/10.1016/j.ymgme.2004.01.... ] Laróvere et al., 2007[2525. Laróvere LE, O’Neill JP, Randall M, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):255-258. doi: 10.1080/15257770701257269 https://doi.org/10.1080/1525777070125726... ] Jinnah et al., 2010[2222. Jinnah HA, Ceballos-Picot I, Torres RJ, et al. Attenuated variants of Lesch-Nyhan disease. Brain. 2010;133(Pt 3):671-689. doi: 10.1093/brain/awq013 https://doi.org/10.1093/brain/awq013... ]
20	13	HND	c.584A>C	p.Y195S		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
21	13	HND	c.584A>C	p.Y195S		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
22	13	HND	c.584A>C	p.Y195S	New case
23	13	HND	c.584A>C	p.Y195S	New case
24	13	HND	c.584A>C	p.Y195S	New case
25	13	HND	c.584A>C	p.Y195S	New case
26	13	HND	c.584A>C	p.Y195S	New case
27	14	HND	c.584A>C	p.Y195S	No knowledge of family history (from mother)	Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
5	5	LND	c.609+6T>G	E8 excluded		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
6	5	LND	c.609+6T>G	E8 excluded		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]
7	6	LND	Exons 4-6 deleted	3 exons deleted		Fu et al., 2014[44. Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain. 2014;137(Pt 5):1282-1303. doi: 10.1093/brain/awt202 https://doi.org/10.1093/brain/awt202... ]

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[1] Corresponding author
Laura Laróvere, Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Hospital de Niños de la Santísima Trinidad Clínica Pediátrica, Centro de Estudio de las Metabolopatías Congénitas, Córdoba, Argentina. E-mail: lauralarovere@hotmail.com, lauraelarovere@gmail.com