Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

Saute, Jonas Alex Morales; Souza, Carolina Fischinger Moura de; Poswar, Fabiano de Oliveira; Donis, Karina Carvalho; Campos, Lillian Gonçalves; Deyl, Adriana Vanessa Santini; Burin, Maira Graeff; Vargas, Carmen Regla; Matte, Ursula da Silveira; Giugliani, Roberto; Saraiva-Pereira, Maria Luiza; Vedolin, Leonardo Modesti; Gregianin, Lauro José; Jardim, Laura Bannach

doi:10.1590/0004-282X20160155

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ARTICLES • Arq. Neuro-Psiquiatr. 74 (12) • Dec 2016 • https://doi.org/10.1590/0004-282X20160155 copy

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

Desfechos neurológicos após transplante de células tronco hematopoiéticas na adrenoleucodistrofia ligada ao X, forma cerebral, na leucodistrofia metacromática de início tardio e na síndrome de Hurler

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Hematopoietic stem cell transplantation (HSCT) is the only available treatment for the neurological involvement of disorders such as late-onset metachromatic leukodystrophy (MLD), mucopolysaccharidosis type I-Hurler (MPS-IH), and X-linked cerebral adrenoleukodystrophy (CALD).

Objective

To describe survival and neurological outcomes after HSCT for these disorders.

Methods

Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated.

Results

Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT.

Conclusion

Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.

hematopoietic stem cell transplantation; leukodystrophy, metachromatic; mucopolysaccharidosis I; adrenoleukodystrophy

Diagnosis; Case	CALD-1	CALD-2	CALD-3	CALD-4	CALD-5	CALD-6	CALD-7	MLD-8b	MLD-9	MPS IH-10	MPS IH-11
Patient sex	Male	Male	Male	Male	Male	Male	Male	Female	Male	Female,	Male
Disease	CALD	CALD+AMN	CALD	CALD	CALD	CALD	CALD	juvenile onset MLD	adult onset MLD	MPS IH	\ MPS IH-11
Age at HSCT indication (years)	8.8	18	6.5	9.5	7.5	6.2	27.5	8.5	19	0.9	0.9 (first HSCT); 2.6 (second HSCT
Age at HSCT (years)	9.4	19.4	8.4	10.8	8.4	6.5	28.2	9.2	20.6	2.2	1.9 (first HSCT); 2.8 (second HSCT)
Donor gender and age (years) at HSCT	Female, 5.2	Male, 31.9	Male, 48	Male, 35.4	Male, newborn	Female, 18.4	Male, 20.3	Female, 27y	Male, 24.4	Male, 34	Female, 33.5
Donor type	Sibling	Uncle	Unrelated	Unrelated	Unrelated	Sibling	Unrelated	Sibling	Sibling	Unrelated	Unrelated
Genotype of related donors	normal VLCFA;	non-carrier;				non-carrier		p.P426L -/- PD analysis -/-	p.P426L -/- PD analysis: c.1524+96A>G / -
HLA donor/recipient match status	HLA identical	HLA identical	HLA identical	HLA identical	HLA mismatched (Cw allele)	HLA identical	HLA mismatched (DQB1 allele)	HLA identical	HLA identical	HLA identical	HLA identical
Conditioning Regimen	Bu and Cy	Bu and Cy	Bu and Cy	Bu and Cy	Bu and Cy	Bu and Cy	Bu and Cy	Bu and Cy	Bu and Cy	Bu and Cy	Bu and Cy
GVH Prophylaxis	MTX and Tacrolimus	CSA and MTX	ATG, CSA, and MTX	ATG, CSA, and MTX	ATG, CSA, and MMF	CSA, and MTX	ATG, CSA, and MTX	CSA and MTX	CSA and MTX	ATG, CSA. and MTX	ATG, CSA. and MTX
Graft source and NC dose (x 10⁸/kg)	BM, 4.1	BM, 5.4	BM, 6.6	BM, 2.9	CB, 16.8	BM, 5.2	BM, 1.8	BM. 7.7	BM, 4.7	BM, 6.2	BM, 4.5
Days to ANC >0.5x10⁹/L	15	19	17	28	15	21	15	22	15	21	19
Latest chimerism (recipient levels of the former cells) and time from HSCT (months)	100%, +62 m	NA	100%, +2 m	100%, +74m	100%, +49 m	100%, +22 m	100%, +7 m	100%, +57 m	100%, +17 m	34%, +46 m	7%, +11 m
Outcome	Favourable	Favourable	Unfavourable	Favourable	Favourable	Favourable	Death 9 months after HSCT (29yo)	Favourable	Unfavourable	Favourable	Death 23 after 2nd HSCT (2.8 yo)
Hb/WBC/PLT at last follow-up (x109/L)	150 / 6.2 / 325	96 / 2.5 / 142	132 / 4.6 / 110	120 / 3.2 / 151	135 / 5.4 / 179	122 / 7.2 / 177	\	127 / 5.0 / 151	115 / 4.7 / 270	129 / 4.5 / 191

Variable	CALD-1	CALD-2	CALD-3	CALD-4	CALD-5	CALD-6	CALD-7	MLD-8b	MLD-9	MPS IH-10	MPS IH-11
Genotype	p.L628Q	p.A232fsX64	p.A232fsX64	p.R518Q	p.S358X	p.A401W	p.P560L	p.P426L/p.P426L; PD negative at ARSA gene	p.P426L/ p.P426L; PD negative at ARSA gene	p.W402X/ p.W402X	p.W402X/ p.W402X
Age at onset of cerebral signs (years)	8.9 Addison-only at 7yo	18	6.5	9.5 Addison-only at 7yo	7.5	6.4	27.5	NA	19	0.8	0.9
Age at HSCT (years)	9.4	19.4	8	10.9	8.4	6.5	28.2	9.1	20.6	2.1	1.9 (first HSCT) and 2.8 (second HSCT)
Neurological and clinical examination findings at the time of HSCT	Asymptomatic	AMN without encephalic manifestations	Ataxia, ankle clonus and attention deficit to auditory stimuli	Asymptomatic	Asymptomatic	Brisk reflexes on the left hemibody	Hemiparesis, dysarthria and a conduction aphasia	Intermittent strabismus	Personality changes, seizures and cognitive loss. Babinski sign on right side	Recurrent upper air infections, hepatomegaly, failure to thrive, developmental delay, and coarse facies. Severe PMD retardation: unable to walk or talk.	Moderate PMD retardation: at the time of first HSCT, still starting to walk and talk.
Age and status at last follow-up (time elapsed)	16yo (7 years after HSCT): No complains Mild signs of neuropathy on neurological examination	27yo (8 years and 9 months after HSCT) ): AMN without encephalic manifestations. Progressive worsening of gait since 18yo (needs canes for walking since 25yo).	9yo (12 months after HSCT) Severe GVHD. Marked worsening: aphasia, tetraparesis	16yo (5 years after HSCT): Stable (clinically normal). NCS disclosed peripheral neuropathy.	13y10m (5 years after HSCT): Stable (asymptomatic)	8y8m (2 years after HSCT): Stable (brisk reflexes on the left hemibody)	29yo (9 months after HSCT): Death due to Chronic GVH + opportunistic infection 9 months after HSCT	16yo (7 years and 6 months after HSCT) Stable. Normal neurological examination. Focal seizures controlled with valproic acid. Subclinical demyelinating polyneuropathy on nerve conduction studies, and slowed P40 latencies at somatosensory evoked responses. Normal visual evoked responses.	22 yo (18 months after HSCT) Akinetic mutism	5y11m (3 years and 8months after HSCT) Stable. No further cognitive losses, Communication was nonverbal, though enough to her daily needs. Coarse facies, weight and height on percentile 3, gibbosity, and joint restriction in hands, arms and legs still present. No hepatomegaly on ultrasound. Thickening of the leaflets of the aortic and mitral valves without changes in transvalvular flow on echocardiogram.	3 years: Death due opportunistic infection at 23 days after 2^nd HSCT
Baseline IQ	Performance 103 Total 96	Performance 105 Total 91	NA	Performance 141 Total 140	Performance 99 Total 86	NA	NA	NA	NA	NA	NA
Last IQ (time elapsed)	Performance 106 Total 105 (5 years later)	NA	NA	Performance 136 Total 123 (2 years later)	Performance 108 Total 105 (2 years later)	NA	NA	NA	NA	NA	NA
Baseline MRI: (CALD-Loes score, MLD-Eichler score)	Loes of 2	Loes of 6.5	Loes of 4.5	Loes of 4.5	Loes of 4	Loes of 3	Loes of 8	Eichler score of 10	Eichler score of 20	WM lesions in the periventricular and deep WM associated with mild ventricular enlargement (Figure 4A-B)	-----
Last MRI: (CALD-Loes score, MLD-Eichler score)	Loes of 1 (7y after HSCT)	Loes of 4 (6 years and 9 months after HSCT)	Loes of 7 (12 months after HSCT)	Loes of 6.5 (5 years and 6 monts after HSCT)	Loes of 4 (5 years after HSCT)	Loes of 7 (2 years after HSCT)	Loes of 8 (2 months after HSCT)	Eichler score of 12 (5 years after HSCT)	NA	Significant reduction of periventricular and deep WM lesions. Mild ventricular enlargement also improved (Figure 4C and D) (3 years after HSCT)	NA
Baseline biochemical markers	C26: 2.2 µmol/L C26/22 ratio 0.04	C26:3.47 µmol/L C26/22 ratio 0.10	C26:2.90 µmol/L C26/22 ratio 0.15	C26: 1.94 µmol/L C26/22 ratio 0.06	C26: 4.33 µmol/L C26/22 ratio 0.049	C26: 3.54 µmol/L C26/22 ratio 0.08	C26: 4.53 µmol/L C26/22 ratio 0.07	ARSA activity in leukocytes: 1 nmol/h/mg prot Urinary sulfatides ++	ARSA activity in leukocytes: undetectable Urinary sulfatides: ++	α-L-iduronidase activity in leukocytes: 0.2 nmol/h/mg prot Urinary GAGs: 532 ug/mg creatinine	α-L- iduronidase activity in leukocytes: 4.0 nmol/h/mg prot Urinary GAGs: 638 ug/mg creatinine
Last biochemical markers(time elapsed)	C26:2.9 µmol/L C26/22 ratio 0.05 ( 6 years)	NA	C26:5.7 µmol/L C26/22 ratio 0.16 (1 month)	C26:1.9 µmol/L C26/22 ratio 0.13 (6 years)	C26: 1.8 µmol/L C26/22 ratio 0.17 (5 years)	C26: 0.7 µmol/L C26/22 ratio 0.12 (2 years)	NA	ARSA activity in leukocytes: 9.5 ml/mg of prot/h Urinary sulfatides ++ (6 years)	ARSA activity in leukocytes: 5.3 nmol/h/mg prot	α-L- iduronidase activity in leukocytes: 22 nmol/h/mg prot Urinary GAGs:185 ug/mg creatinine	α-L- iduronidase activity in leukocytes: 12 nmol/h/mg prot Urinary GAGs:289 ug/mg creatinine

Factors	All	Favorable outcome	Unfavorable outcome

			Death due to HSCT or worsening of clinical picture
	11	7	4 (2 CALD, 1 MLD, 1 MPS-IH)
HSCT related donor	5	4	1
HSCT unrelated donor	6	3	3 (two deaths)
Adult-onset disease	2	0	2 (one MLD and one CALD)
Loes score at the time of HSCT, in CALD	7 (2 to 8)	4 (2 to 6.5)	6.25 (4.5 and 8)
Mean (range)	7 (2 to 8)	4 (2 to 6.5)	6.25 (4.5 and 8)
Disease duration before HSCT *, in years	0.94 (0 to 1.6)	0.8 (0 to 1.4)	1.2 (0.7 to 1.6)
Mean (range)	0.94 (0 to 1.6)	0.8 (0 to 1.4)	1.2 (0.7 to 1.6)

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[1] Correspondence: Laura Bannach Jardim; Serviço de Genética Médica do Hospital de Clinicas de Porto Alegre; Rua Ramiro Barcelos, 2350; 90035-903 Porto Alegre RS, Brasil; Email: ljardim@hcpa.edu.br