Boucher Neuhäuser syndrome – two novel cases and review of the literature Tarnutzer et al. 2014

Supplement 2: clinical features of identified cases (in alphabetical order)

Study / # / Sex, cons-ang. ** / Age
(first sx / at exam) (y) / Imaging / Genetics / Neurological symptoms and signs / Ophthalmological sx / Endocrinological sx
Ataxia, age of onset (y) / DA / Ocular motor sx / PT sx II / PNP ¶ / NP
sx / Visual loss / VA OD/OS
(age of onset, y) / (chorio-) retinal dystrophy / color vision /visual field defects / Hypogon. hypo-gonadism / amenorrhea (1°/2°) / Stature (normal/ short)
Arrambide 2008 [1] / 1 / M, NR / 20 / 28, ataxia / cerebellar atrophy. T2 hyperintens. PV / brainstem / spinal (MRI) / NR / 20 / + / NR / + / + / NR / NR / NR (NR) / + / NR / NR / + / NA / normal
Baroncini 1991 [2] / 2 / M, no / 6 / 33,
visual loss / NR / NR / 25 / + / hor. N / - / - / - / + /0.1/0.1 (6) / + / NR / + / + / NA / normal
3 / M, no / 6 / 31,
visual loss / mild cerebral / cerebellar atrophy (CT) / NR / 24 / NR / NR / NR / NR / - / + /1.0/1.0 (6) / + / Intact / NR / + / NA / short
Barrientos 1997 [3] / 4 / F, NR / NR / 39, amenor-rhea / marked cerebellar atrophy (H / V) (MRI) / 5.5kb mtDNA deletion / 31 / NR / NR / NR / NR / NR / + / severely reduced bilat (36) / + / NR / NR / + / 1° / normal
Bernard-Weil 1962 [4] / 5 / M, NR / NR / 34,
NR / NR / NR / 30 / NR / NR / + / NR / NR / NR / NR (NR) / + / NR / NR / + / NA / NR
Boucher 1969 [5] / 6 / F, no / 4 / NR,
visual loss / NR / NR / 34 / - / N / + / - / NR / + / LP OU (4) / + / NR / NR / + / 1° / normal
7 / F, no / 12 / 15,
visual loss / NR / NR / Btw 12 and 15 / NR / mild N, upward gaze red. / + / - / NR / + / reduced OU (12) / + / NR / NR / + / 1° / short
Erdem 1994 [6] / 8 / M, yes 1st CS / 12 / 27,
ataxia / cerebellar atropy (H, deep nuclei, V) (MRI) / NR / 12 / + / GEN / - / - / Red. IQ / + / CF/ 0.75 (12) / + / None / + / + / NA / normal
Fok 1989 [7] / 9 / M, no / 8 / 18,
ataxia / cerebellar atrophy (H) (CT) / NR / 8 / NR / GEN / - / - / NR / NR / NR (NR) / + / NR / NR / + / NA / short
Jbour 2003 [8] / 10 / M, yes / 6 / 21,
ataxia / cerebellar atrophy (H / V) (MRI) / NR / 6 / + / multidir. N, hypom. S / - / - / Red. IQ / + / 0.25/0.25 (NR) / + / Intact / NR / + / NA / short
11 / F, yes / 6 / 17,
ataxia / cerebellar atrophy (H) (MRI) / NR / 6 / + / multidir. N, hypom. S / - / - / Red. IQ / + / 0.67/0.5 (NR) / + / Intact / NR / + / 1° / short
12 / F, yes / 6 / 14,
ataxia / cerebellar atrophy (H) (MRI) / NR / 6 / + / multidir. N, hypom. S / - / - / Red. IQ / + / 0.33/0.33 (NR) / + / Intact / NR / + / 1° / short
Kate 2011 [9] / 13 / M, yes 2nd CS / 20 / 22,
ataxia / marked difuse cerebellar atrophy, T2-hyperintens. PV (MRI) / neg. (SCA 1/2/3, FRDA) / 20 / + / none / - / - / Red. IQ / + / 1.0/1.0 (NR) / + / NR / NR / + / NA / short
14 / F, yes 2nd CS / 18 / NR,
ataxia / difuse cerebellar atrophy, T2-hyperintens. PV (MRI) / NR / 18 / + / none / - / NR / Red. IQ / NR / NR (NR) / + / NR / NR / + / 1° / NR
Limber 1989 [10] / 15 / F, no / 15 / 33,
amenor-rhea / NR / NR / 27 / - / DBN, GEN / + / - / - / + / 0.2/0.2 (20) / + / Red. / + / + / 1° / short
16 / M, no / Early CH / NR, delayed puberty / slight cerebellar atrophy (CT) / NR / Early CH / + / Vert. N., GEN / + / - / - / + / 0.3/0.1 (early CH) / + / Intact / + / + / NA / short
17* / F, yes 2nd CS / 33 / 69,
visual loss / NR / NR / Btw 33 and 38 / + / Vert. N.
GEN / + / - / Red. IQ / + / 0.67/0.5 (NR) / + / NR / + / + / 1° / normal
Ling 2009 [11] / 18 / M, no / 39 / 45,
visual loss / cerebellar atrophy (esp. V), putaminal / midbrain atrophy (MRI) / NR / NR / NR / NR / - / + / - / + / reduced bilat (39) / + / NR / NR / + / NA / normal
Neuhäuser 1975 [12] † / 19 / F, yes 2nd CS / 12 / 53,
visual loss / NR / NR / 12 / NR / NR / NR / NR / NR / + / blind OU (NR) / + / NR / NR / + / 1° / NR
Nuti 2004 [13] / 20 / M, NR / 40 / 64,
ataxia / cerebellar atrophy (MRI) / NR / 40 / + / NR / + / - / NR / NR/ NR (NR) / + / NR / NR / + / NA / normal
Rizzi 1998 [14] / 21 / M, no / 6 / 38,
visual loss / diffuse cerebellar atrophy (CT) / neg. (SCA 1/2/3, FRDA, mtDNA) / 20 / NR / GEN / + / - / NR / + / LP OU (6) / + / NR / NR / + / NA / normal
22 / M, no / 18 / 36,
delayed puberty / diffuse cerebellar atrophy, bilat. frontal atrophy (CT) / neg. (SCA 1/2/3, FRDA, mtDNA) / 24 / + / GEN / NR / NR / NR / + / 0.7/0.2 (24) / + / NR / NR / + / NA / short
Rump 1997 [15] / 23 / M, no / 24 / 30,
visual loss / cerebellar atrophy (esp. superior / dorsal V) (MRI) / NR / CH / NR / none / NR / - / NR / + / 0.1/0.5 (23) / + / Red. / + / + / NA / normal
24 / F, no / 21 / 24, amenor-rhea / cerebellar atrophy (esp. superior / dorsal V) (MRI) / neg. for mtDNA / CH / NR / vert. N.,
GEN / NR / + / NR / + / 0.5/0.5 (21) / + / Red. / + / + / 1° / normal
Salvador 1995 [16] / 25 / F, no / 17 / 39, amenor-rhea / diffuse atrophy cerebellar H (MRI) / NR / 28 / + / vert. N.,
GEN / NR / NR / - / + / 0.2/0.33 (37) / + / Red. / + / + / 1° / NR
Santos 2003 [17] / 26 / M, yes 1st CS / NR / 34,
delayed puberty / cerebellar atrophy (esp. superior / dorsal V), T2-hyperintens. PV (MRI) / neg. (SCA 1/2/6, mtDNA) / NR / + / NR / NR / - / NR / NR / NR (NR) / + / NR / - / + / NA / NR
Synofzik 2014 [18]
*** / 27 / F, NR / 2 / 56,
visual loss / cerebellar / pontine atrophy (MRI) / PNPLA6 both allels / 6 / + / GEN, saccadic SPEM / - / NR # / MCI / +/ NR (2) / + / NR / - / + / 1° / NR
28 / M, NR / 3 / 55,
visual loss / cerebellar / pontine atrophy (MRI) / PNPLA6 both allels / 6 / + / GEN, saccadic SPEM / - / NR # / MCI / +/ NR (3) / + / NR / - / + / NA / NR
29 / F, NR / 1 / 53,
visual loss / cerebellar / pontine atrophy (MRI) / PNPLA6 both allels / 7 / + / GEN, saccadic SPEM / - / NR # / MCI / +/ NR (1) / + / NR / - / + / 1° / NR
30 / F, NR / 2,5 / 48,
visual loss / cerebellar / pontine atrophy (MRI) / PNPLA6 both allels / 7 / + / GEN, saccadic SPEM / - / NR # / MCI / +/ NR (2.5) / + / NR / - / + / 1° / NR
31 / F, NR / 12 / 44,
visual loss / cerebellar atrophy (MRI) / PNPLA6 both allels / 27 / + / GEN, saccadic SPEM / + / NR # / MCI / +/ <0.05 OU (12) / + / NR / - / + / 1° / NR
32 / F, NR / 6 / 42,
ataxia / cerebellar atrophy (MRI) / PNPLA6 both allels / 6 / + / GEN, saccadic SPEM / + / NR # / MCI / - / 1.0 OU (NA) / - / NR / - / + / 1° / NR
33 / M, NR / 6 / 61,
ataxia / cerebellar atrophy (MRI) / PNPLA6 both allels / 6 / + / GEN, saccadic SPEM / - / NR # / - / + / 0.2 OU (16) / + / NR / NR / + / NA / NR
34 / M, NR / 6 / 57,
ataxia / cerebellar atrophy (MRI) / PNPLA6 both allels / 6 / + / GEN, saccadic SPEM / + / NR # / - / + / 0.2 OU (16) / + / NR / NR / + / NA / NR
35 / M, NR / 14 / 26,
delayed puberty / cerebellar atrophy (MRI) / PNPLA6 both allels / 20 / + / GEN, saccadic SPEM / - / - / - / + / <0.1/0.2 (14) / + / NR / - / + / NA / NR
Tojo 1995 [19] / 36‡ / F, yes 2nd CS / 35 / 57,
amenor-rhea / cerebellar atrophy (incl. superior V, sparing of inferior V) (MRI) / NR / 35 / + / NR / - / - / - / + / 0.1/0.1 (NR) / + / NR / NR / + / 2° / NR
Umehara 2010 [20] / 37 / M, yes 2nd CS / 30 / NR,
ataxia / NR / NR / 30 / + / saccadic SPEM / NR / - / NR / + / NR (43) / + / NR / + / + / NA / NR
38 / F, yes 2nd CS / 15 / NR,
amenor-rhea / cerebellar atrophy (incl. superior V, sparing of inferior V) (MRI) / Neg. (SCA 1/2/3/6/7/8/12, DRPLA) / 38 / + / saccadic SPEM / NR / + / NR / + / NR (48) / + / NR / + / + / 1° / NR
39§ / F, yes 2nd CS / 20 / 52,
ataxia / cerebellar atrophy (incl. superior V, sparing of inferior V) (MRI) / Neg. (SCA 1/2/3/6/7/8/17, DRPLA) / 20 / + / saccadic SPEM,
GEN / - / + / - / + / 0.1/0.1 (46) / + / NR / + / + / 1° / short
Yu 2008 [21] / 40 / M, NR / 12 / 18,
visual loss / cerebellar atrophy (H / V) (MRI) / NR / 16 / NR / vert. N.,
GEN / NR / NR / - / + / 0.1/0.1 (12) / + / Red. / + / + / NA / normal
index case #1(this study) / 41 / M, no / 4 / 28,
ataxia / marked cerebellar atrophy (esp. superior / dorsal V), pontine atrophy, T2-hyperintens. PV / pontine PT), empty sella (MRI) / PNPLA6 both alleles / 4 / + / DBN, GEN/ RBN, saccadic SPEM, no OKN / + / - / red. attention, red. cognitive flexibility, mild psycho-motor slowing / + / 0.6/0.8 (25) / + / NR / + / + / NA / normal
Index case #2 (this study) / 42 / M, no / 13/ 36,
delayed puberty / marked cerebellar atrophy (H / V), empty sella (MRI) / PNPLA6 both allels / 32 / + / GEN, saccadic SPEM, red. OKN, red. VOR- supression / - / (+) / red. spilt attention, red. short term and working memory, red. cognitive flexibility / - /
1.25/ 1.25
(NA) / + (maculo-pathy bilateral) / NR / NR / + / NA / normal

Abbreviations

DA=dysarthria; CF=counting fingers; CH=childhood; CRD=chorio-retinal dystrophy; CS=cousins; DBN=downbeat nystagmus; DRPLA=dentato-rubro pallido-luysian atrophy; EPT=extrapyramidal tract; FRDA=Friedreich Ataxia; GEN=gaze-evoked nystagmus; H=hemispheres; LP=light perception; mtDNA=mitochondrial DNA; N=nystagmus; NA=not applicable; NP=neuropsychological; NR=not reported, IQ=intelligence quotient; OD=right eye; OKN=optokinetic nystagmus; OS= left eye; OU= both eyes, PNP=polyneuropathy; PT=pyramidal tract; RBN=rebound nystagmus; red=reduced; S=saccades; SCA=spino-cerebellar ataxia; SEM=saccadic eye movements; SPEM=smooth pursuit eye movements; V=vermis; VA=visual acuity; VP=periventricular; VFC=visual field constrictions; VOR=vestibulo-ocular reflex.

* Case previously described by Neuhäuser and Opitz [12], information of both case descriptions pooled

** Cases with the gender (M or F) in italic letters were siblings.

*** Cases originated from four different families, with #27-30 (family identifier: IHG25190), #28-29 (family identifier: ARCA-05) and #30-31 family identifier IHG25353) being siblings.

† Case series of four siblings, with cases one (#17) and two (#19) included here. In addition, Neuhäuser and Opitz [12] described two brothers with ataxia and hypogonadism, but vision problems were either not stated (case 3) or were not present (case 4). Therefore these cases were not included in this review.

‡ This is case 2 reported by Tojo et al. [19]

§ This case was previously described by Ichinose and colleagues [22] and Tojo and colleagues [19] (case 1). Information from these three publications was pooled.

II Positive if any combination of these signs was present: increased deep tendon reflexes („brisk“), ankle cloni, plantar response being extensor, spastic muscle tone

¶ For a diagnosis of PNP clinical findings as reduced / absent DTRs and / or sensory deficits had to be confirmed either by abnormal ENMG or pathological nerve biopsy.

# No reports on sensory disturbances, but mentioning of reduced / lacking patellar tendon reflex and / or achilles tendon reflex.

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Boucher Neuhäuser syndrome – two novel cases and review of the literature Tarnutzer et al. 2014

References

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Boucher Neuhäuser syndrome – two novel cases and review of the literature Tarnutzer et al. 2014

1. Arrambide G, Moreno A, Marques JM, Leyva A (2008) Boucher-Neuhäuser Syndrome: a case report. Posterpresentation at EFNS-Meeting 2008. Eur J Neurol 15:179

2. Baroncini A, Franco N, Forabosco A (1991) A new family with chorioretinal dystrophy, spinocerebellar ataxia and hypogonadotropic hypogonadism (Boucher-Neuhauser syndrome). Clin Genet 39:274-277

3. Barrientos A, Casademont J, Genis D, Cardellach F, Fernandez-Real JM, Grau JM, Urbano-Marquez A, Estivill X, Nunes V (1997) Sporadic heteroplasmic single 5.5 kb mitochondrial DNA deletion associated with cerebellar ataxia, hypogonadotropic hypogonadism, choroidal dystrophy, and mitochondrial respiratory chain complex I deficiency. Hum Mutat 10:212-216

4. Bernard-Weil E, Endtz LJ (1962) Sur un cas familial de degeneration spino-cerebelleuse avec eunuchoidisme hypogonadotrophique considerations pathogeniques et methodologiques. Nouv Presse Med 70:524-526

5. Boucher BJ, Gibberd FB (1969) Familial ataxia, hypogonadism and retinal degeneration. Acta Neurol Scand 45:507-510

6. Erdem E, Kiratli H, Erbas T, Varli K, Eldem B, Akalin S, Tan E, Topaloglu H, Gedikoglu G (1994) Cerebellar ataxia associated with hypogonadotropic hypogonadism and chorioretinopathy: a poorly recognized association. Clin Neurol Neurosurg 96:86-91

7. Fok AC, Wong MC, Cheah JS (1989) Syndrome of cerebellar ataxia and hypogonadotrophic hypogonadism: evidence for pituitary gonadotrophin deficiency. J Neurol Neurosurg Psychiatry 52:407-409

8. Jbour AK, Mubaidin AF, Till M, El-Shanti H, Hadidi A, Ajlouni KM (2003) Hypogonadotrophic hypogonadism, short stature, cerebellar ataxia, rod-cone retinal dystrophy, and hypersegmented neutrophils: a novel disorder or a new variant of Boucher-Neuhauser syndrome? J Med Genet 40:e2

9. Kate MP, Kesavadas C, Nair M, Krishnan S, Soman M, Singh A (2011) Late-onset Boucher-Neuhauser Syndrome (late BNS) associated with white-matter changes: a report of two cases and review of literature. J Neurol Neurosurg Psychiatry 82:888-891

10. Limber ER, Bresnick GH, Lebovitz RM, Appen RE, Gilbert-Barness EF, Pauli RM (1989) Spinocerebellar ataxia, hypogonadotropic hypogonadism, and choroidal dystrophy (Boucher-Neuhauser syndrome). Am J Med Genet 33:409-414

11. Ling H, Unnwongse K, Bhidayasiri R (2009) Complex movement disorders in a sporadic Boucher-Neuhauser Syndrome: Phenotypic manifestations beyond the triad. Mov Disord 24:2304-2306

12. Neuhauser G, Opitz JM (1975) Autosomal recessive syndrome of cerebellar ataxia and hypogonadotropic hypogonadism. Clin Genet 7:426-434

13. Nuti A, Caneparo D, Martinelli P, Lambelet P, Berti C, Del Dotto P, Bonuccelli U (2004) Boucher–Neuhauser syndrome with neutrophils hypersegmented: A multisystem disorder? Posterpresentation at EFNS-Meeting 2004. Eur J Neurol 11:117