MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis.

BACKGROUND AND PURPOSE: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N-acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging. MATERIALS AND METHODS: Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population. RESULTS: Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. CONCLUSIONS: Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions.

Molecularly defined interstitial tandem duplication 6p case with mild manifestations.

An interstitial tandem duplication of 6p21.1-p22.2 was found in a girl at 11 months of age when she was evaluated for developmental delay. Previous cases reported with partial 6p duplication usually have involved terminal duplications, with breakpoints ranging from 6p11 to 6p25. Our patient exhibits a milder phenotype compared to the previously reported cases in the literature. Features that she has in common with the other cases include craniofacial anomalies, such as broad nasal bridge and bulbous tip, thin lips, incomplete development of the scapha helix bilaterally, mild spastic paraparesis of the lower extremities, gross motor delay, and mild cognitive delays.

Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood.

Neuronal ceroid lipofuscinoses (NCLs) are the most common hereditary neurodegenerative diseases of childhood. The infantile form, INCL, is caused by lysosomal palmitoyl-protein thioesterase (PPT) deficiency, which impairs the cleavage of thioester linkages in palmitoylated proteins, preventing their hydrolysis by lysosomal proteinases. Consequent accumulation of these lipid-modified proteins (constituents of ceroid) in lysosomes leads to INCL. Because thioester linkages are susceptible to nucleophilic attack, drugs with this property may have therapeutic potential for INCL. We report here that two such drugs, phosphocysteamine and N-acetylcysteine, disrupt thioester linkages in a model thioester compound, [14C]palmitoyl approximately CoA. Most importantly, in lymphoblasts derived from INCL patients, phosphocysteamine, a known lysosomotrophic drug, mediates the depletion of lysosomal ceroids, prevents their re-accumulation and inhibits apoptosis. Our results define a novel pharmacological approach to lysosomal ceroid depletion and raise the possibility that nucleophilic drugs such as phosphocysteamine hold therapeutic potential for INCL.

Isolated bilateral anophthalmia in a girl with an apparently balanced de novo translocation: 46,XX,t(3;11)(q27;p11.2).

Primary anophthalmos is a heterogeneous condition. In its nonsyndromal form, it is usually considered an autosomal recessive trait. However, other causes such as chromosomal abnormalities and prenatal insults need to be considered. We report on a unique reciprocal translocation 46,XX,t(3;11)(q27;p11.2) in a baby with isolated anophthalmos. Both Chitayat et al. [1996] and Alvarez Arratia et al. [1984] have reported on cases of terminal deletion of the long arm of chromosome 3. In each case the child had multiple anomalies including microphthalmia or anophthalmia. Because our patient appears to have no other anomalies, this break point may indicate that a genetic locus for eye formation exists at chromosome site 3q27. Published 1999 Wiley-Liss, Inc.

Rare interstitial deletion (2)(p11.2p13) in a child with pericentric inversion (2)(p11.2q13) of paternal origin.

An unbalanced 46,XY,der(2)del(2)(p11.2p13) inv(2)(p11.2q13) karyotype was found in a phenotypically abnormal child with a de novo interstitial deletion of band 2p12 associated with an inv(2)(p11.2q13) inherited from the father. The inv(2) is generally considered a benign familial variant without significant reproductive consequences. However, our findings led us to consider a previously proposed mechanism of unequal meiotic crossing over at the base of a parental inversion loop, which could lead to either a deletion or duplication of a segment adjacent to the inverted region in the offspring. This phenomenon has been reported in other inversions of chromosomes 1, 7, 13, 15, and 17 and may explain the origin of the deletion in our patient. Although repetitive sequences might be present around such inversions, which could predispose to de novo deletions independently of the inversion, current evidence including this case favors a proposed causal relationship between the parental inversion and the deletion in the child. Our review and results suggest there could be a small risk for a related imbalance to couples with an inv(2)(p11.2q13). For del(2)(p11.2p13), which is rare, a more distinct phenotype has been proposed herein. Our patient shared several findings with the three previously published cases, namely the broad nasal bridge, abnormal ears, high-arched palate, psychomotor retardation, and micrognathia. However, our patient also had sensorineural hearing loss and significant hypotonia, which have not been previously reported, thereby expanding our understanding of this rare deletion. Am. J. Med. Genet. 87:139-142, 1999. Published 1999 Wiley-Liss, Inc.

Duplication of the pituitary gland as shown by MR.

Duplication of the pituitary gland is a rare malformation. The authors describe a patient with features of the median cleft face syndrome (hypertelorism, V-shaped hairline, and developmental delay) who exhibited duplication of the pituitary gland and diffuse thickening of the hypothalamus (hypothalamic hamartoma) as shown by MR. The embryology of the developing pituitary gland and pathogenesis of pituitary duplication are discussed.

Amino acid composition and N-terminal sequence of purified cystine binding protein of Escherichia coli.

Cystine Binding Protein (CBP), a commercially available crude protein extract obtained by osmotic shock of Escherichia coli (E. coli), was studied to characterize further its cystine binding properties and to elucidate its cystine transport activity. We report here the amino acid composition, the N-terminal amino acid sequence analysis and some binding characteristics of the purified cystine binding component of CBP. A search of the Swiss-Prot version 20 data base revealed that this sequence is unique.

A histidine binding protein ofEscherichia coli: a component of cystine binding protein ofEscherichia coli.

Commercially obtained cystine binding protein (CBP), an osmotic shock protein ofEscherichia coli, was studied in an effort to determine its binding characteristics. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS/PAGE) analysis of commercially obtained CBP showed three protein bands. N-terminal amino acid microsequencing and subsequent computer search revealed that the sequence of one of these proteins (25-kDa) was nearly identical to histidine binding protein (HisJ) ofSalmonella typhimurium. Purification of CBP by HPLC yielded four protein peaks, of which one bound histidine exclusively. Binding was maximal at pH 5.0 to 6.0, at 4°C, did not require calcium or magnesium ions and was not inhibited by reduction of CBP disulfide bonds. Amino acids other than histidine or cystine did not bind to CBP. These data show that commercially available CBP is not a homogenous protein; it contains a histidine as well as a cystine binding component.

Terminal transverse limb defects associated with familial cavernous angiomatosis.

Terminal transverse limb defects rarely are reported as familial. Multiple pathogenetic mechanisms, including vascular disruption, have been proposed to account for these defects. We report on a family followed over the past 6 years known to have familial cavernous angiomatosis in which 2 relatives have similar terminal transverse defects at the mid-forearm. Multiple relatives have had episodic bleeding from intracranial cavernous angiomas, a distinct finding in this disorder. Other findings in this family include retinal cavernous angiomas (2 patients), a high incidence of skin angiomas (12 patients), cavernous angiomas of the soft tissue (2 patients), and a hepatic angioma (one patient). One of the 2 individuals with the limb defect was evaluated extensively. Magnetic resonance imaging of the forearm with the terminal transverse defect using gadolinium-DTPA enhancement showed abrupt termination of all structures distal to the normal radial and ulnar heads. We propose that familial cavernous angiomatosis may be a new cause of vascular disruption resulting in terminal transverse limb defects.

Acrofacial dysostosis with ambiguous genitalia.

We report on a 46,XY infant with mandibulofacial dysostosis, preaxial and postaxial limb anomalies, urethral stenosis with left hydronephrosis, and ambiguous genitalia with phallic/scrotal transposition. This infant with atypical pre/postaxial acrofacial dysostosis (AFD) is the first to be reported with ambiguous genitalia. The acrofacial dysostoses are a heterogenous group of disorders characterized by varying degrees of mandibulofacial dysostosis with acral limb defects and may represent a polytopic field defect. These disorders have generally been separated on the basis of their limb anomalies into preaxial, postaxial, lethal, and atypical types. Most cases are sporadic, but various causes have been postulated including autosomal dominant and recessive inheritance, a chromosome 2q duplication, and a possible case of diabetic embryopathy. We review the nonfacial/limb anomalies in other cases of AFD and compare them to those of our case, thereby expanding the spectrum of anomalies in these disorders.

Proteus syndrome.

The term Proteus syndrome was coined in 1983 to describe a disorder of skeletal, hamartomatous, and other mesodermal malformations. The syndrome was named after the Greek god Proteus, whose name means "the Polymorphous." Clinical features of this new syndrome are currently being defined. Including the case reported herein, we have found 34 patients with Proteus syndrome described in the English literature. Major clinical findings, defined as those findings seen in more than half of the cases, include hemihypertrophy, macrodactyly, exostoses, epidermal nevi, characteristic cerebriform masses involving the plantar or palmar surfaces, a variety of subcutaneous masses, and scoliosis. Histologic examination of subcutaneous masses has identified a variety of lipomatous, hamartomatous, and angiomatous tumors.

Inhibition of thrombin-induced platelet aggregation by uteroglobin.

Uteroglobin, a steroid-dependent, small molecular weight (15K) protein in the rabbit, inhibited thrombin-induced aggregation of both rabbit and human gel-filtered platelets (GFP). GFP aggregation by arachidonic acid was not affected by uteroglobin. There were no effects of uteroglobin on thrombin-induced clotting of plasma or purified fibrinogen, or inhibition of thrombin by antithrombin III. Additionally, preliminary results suggest that uteroglobin does not interfere with binding of thrombin to platelets. We suggest that inhibition of platelet aggregation by uteroglobin may function in preventing thrombosis and ensuring free flow of blood through the microvasculature of the uterus and the placenta and may induce some of the antimotility effects of progesterone on the uterus.

Human leg heating using a mini-annular phased array.

The energy deposition pattern within an isolated human leg heated with a mini-annular phased array (MAPA) hyperthermia applicator has been determined. The non-tumor-bearing lower portion of a human leg amputated at the hip due to the presence of a large tumor in the thigh was "fixed" in a 50% ethanol in 0.9% saline solution. Subsequent to this fixation process, the leg was rehydrated in 0.9% saline and heated four times using a MAPA operating at 122 MHz. Specific absorption rates and electric field strengths were calculated from the rates of change of temperature with time measured at 143 different anatomical locations within the leg. When the leg was coaxial with the MAPA and the MAPA was axially positioned midway between the knee and the ankle, the points of maximum heating were skewed away from the center of the MAPA, towards the ankle of the leg and along the central axis of the MAPA. Significant temperature rise was measured inside the bone and the fat as well as inside the muscle of the leg. Bone heating was reduced when the leg was shifted away from the MAPA axis.

Uteroglobin inhibits phospholipase A2 activity.

Although progesterone is known to produce quiescence in the mammalian uterus, the mechanism of this effect is not clearly understood. Here, we report that uteroglobin, a progesterone-induced small molecular weight (16K) protein, inhibits phospholipase A2(PLA2) derived from porcine pancreas as well as from the RAW 264.7 macrophage cell line. We speculate that progesterone may exert its antimotility effects on the uterus via uteroglobin which, by inhibiting PLA2, decreases arachidonic acid release and subsequently reduces prostaglandin levels in this organ. This may explain why progesterone is so vital for the maintenance of pregnancy in almost all mammals.

Intrauterine growth retardation induced by thiamine deficiency and pyrithiamine during pregnancy in the rat.

The role of nutritional factors in the development of prenatal and postnatal growth retardation is not well understood. We tested if thiamine deficiency may cause intrauterine growth retardation in rats. From the second day of gestation Sprague-Dawley rats were freely fed either a nutritionally complete or a thiamine-deficient diet. A similar group of rats was pair-fed with a complete or a thiamine-deficient diet and daily pyrithiamine injections (50 micrograms/100 gm of body weight) were given to precipitate thiamine deficiency during the short gestation of the rat. Maternal thiamine levels in blood and brain tissues, maternal erythrocyte transketolase activity with thiamine pyrophosphate effects, and fetal tissue thiamine levels were measured. The results indicate that feeding a thiamine-deficient diet in conjunction with pyrithiamine injections caused sufficient thiamine deficiency to induce intrauterine growth retardation in the progeny. We conclude that thiamine deficiency alone during in utero development in the rat may contribute to intrauterine growth retardation.

Intrauterine growth retardation caused by dietary biotin and thiamine deficiency in the rat.

The effects on fetal development of maternal biotin deficiency, alone and in conjunction with thiamine deficiency, were investigated in rats. Fetuses from dams given biotin-deficient diet throughout gestation demonstrated only some characteristics of intrauterine growth retardation (IUGR) including abnormal liver weight and a higher brain/liver ratio. However, fetuses from dams given biotin-thiamine-deficient diet and daily pyrithiamine (a thiamine antagonist used to insure thiamine deficiency) injections demonstrated severe IUGR along all of the fetal parameters investigated. We conclude that biotin and thiamine deficiency during intrauterine growth of the fetus may be partially responsible for the development of IUGR, a frequent concomitant of fetal alcohol syndrome.

Balanced rearrangement of chromosomes 2, 5, and 13 in a family with duplication 5q and fetal loss.

We have studied a family in which a mother and daughter (the proposita) had the karyotype 46,XX,ins(2;5),t(5;13). The mother had four spontaneous abortions, a mentally retarded son with duplication (5q), and a daughter who died at 3 months. The proposita had a phenotypically abnormal abortus. Rearrangements involving several chromosomes are very rare. Observations on this family are consistent with the predicted high likelihood of reproductive loss.