Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9

Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroimaging and genetic findings. Individuals with PCH type 9 (PCH9) have a unique combination of postnatal microcephaly, hypoplastic cerebellum and pons, and hypoplastic or absent corpus callosum. PCH9 is caused by biallelic variants in AMPD2 encoding adenosine monophosphate deaminase 2; however, a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63). We identified homozygous or compound heterozygous AMPD2 variants in eight PCH-affected individuals from six families. The eight variants likely affect function and comprise one frameshift, one nonsense and six missense variants; seven of which were novel. The main clinical manifestations in the eight new patients and 17 previously reported individuals with biallelic AMPD2 variants were postnatal microcephaly, severe global developmental delay, spasticity, and central visual impairment. Brain imaging data identified hypomyelination, hypoplasia of the cerebellum and pons, atrophy of the cerebral cortex, complete or partial agenesis of the corpus callosum and the "figure 8" shape of the hypoplastic midbrain as consistent features. We broaden the AMPD2-related clinical spectrum by describing one individual without microcephaly and absence of the characteristic "figure 8" shape of the midbrain. The existence of various AMPD2 isoforms with different functions possibly explains the variability in phenotypes associated with AMPD2 variants: variants leaving some of the isoforms intact may cause SPG63, while those affecting all isoforms may result in the severe and early-onset PCH9.

脑桥小脑发育不全（PCH）是一组常染色体隐性遗传的进行性神经退行性疾病，在产前发病。根据临床、神经影像学和遗传学发现，PCH分为11种亚型。PCH 9型（PCH9）患者具有出生后小头畸形、小脑和脑桥发育不全以及胼胝体发育不全或缺失的独特组合。PCH9是由编码腺苷一磷酸脱氨酶2的AMPD2基因的双等位基因变异引起的；然而，最近在两个患有痉挛性截瘫63型（SPG63）的家庭成员中报道了一种纯合的AMPD2移码变异。我们在来自6个家庭的8名受PCH影响的个体中鉴定出纯合或复合杂合的AMPD2变异。这8种变异可能影响功能，包括1种移码变异、1种无义变异和6种错义变异；其中7种是新的。8名新患者和17名先前报道的具有双等位基因AMPD2变异的个体的主要临床表现为出生后小头畸形、严重的全面发育迟缓、痉挛和中枢性视力障碍。脑部影像学数据显示髓鞘发育不良、小脑和脑桥发育不全、大脑皮质萎缩、胼胝体完全或部分发育不全以及发育不全的中脑呈“8”字形是一致的特征。我们通过描述一名没有小头畸形且中脑没有特征性“8”字形的个体，拓宽了与AMPD2相关的临床谱。具有不同功能的各种AMPD2异构体的存在可能解释了与AMPD2变异相关的表型变异性：使一些异构体保持完整的变异可能导致SPG63，而影响所有异构体的变异可能导致严重且早发的PCH9。